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Fatma, H.; Jameel, M.; Siddique, H.R. Phytochemicals in Redox Homeostasis. Encyclopedia. Available online: https://encyclopedia.pub/entry/43356 (accessed on 10 July 2025).
Fatma H, Jameel M, Siddique HR. Phytochemicals in Redox Homeostasis. Encyclopedia. Available at: https://encyclopedia.pub/entry/43356. Accessed July 10, 2025.
Fatma, Homa, Mohd Jameel, Hifzur R. Siddique. "Phytochemicals in Redox Homeostasis" Encyclopedia, https://encyclopedia.pub/entry/43356 (accessed July 10, 2025).
Fatma, H., Jameel, M., & Siddique, H.R. (2023, April 24). Phytochemicals in Redox Homeostasis. In Encyclopedia. https://encyclopedia.pub/entry/43356
Fatma, Homa, et al. "Phytochemicals in Redox Homeostasis." Encyclopedia. Web. 24 April, 2023.
Phytochemicals in Redox Homeostasis
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This entry is adapted from the peer-reviewed paper 10.3390/chemistry5010017

Redox homeostasis, a dynamic process ensuring a balance between cellular oxidizing and reducing reactions, is crucial for maintaining healthy cellular physiology and regulating many biological processes, requiring continuous monitoring and fine-tuning. Reactive species play a critical role in intra/intercellular signaling, and each cell has a specific system guarding cellular redox homeostasis. Reactive oxygen species (ROS) signaling and oxidative stress are involved in cancer initiation and progression.

redox homeostasis antioxidant reactive species phytochemicals

1. Phytochemicals as a Chemopreventive Agent

Reactive species are known to have a double edge role in carcinogenesis. The level of reactive species is said to play an important role in cancer progression or tumor suppression. It has been observed that at a certain level, reactive species facilitate cancer growth and proliferation, while above that level, reactive species are implicated in the suppression of tumor cells (Table 1). Several studies have pointed toward the cytotoxic role of reactive species in tumor cells. Dietary phytochemicals have drawn much attention because of their extensive therapeutic effects in preventing the onset and progression of a disease. Phytochemicals and their derivatives have been thought to be involved in chemoprevention and chemosensitization, and their therapeutic efficacy has been extensively studied [1]. Many plants have shown anticancer properties owing to the phytochemicals present in them. More than 15 Allium spp. have shown anticancer properties due to their secondary metabolites. Allium spp. contain S-allyl mercaptocysteine, Quercetin, Flavanoids, and Ajoene, which facilitate cytotoxicity, immunomodulation, anti-inflammation, and apoptosis in various cancers. Moreover, these compounds also balance cellular redox homeostasis by scavenging ROS, reducing macromolecular damage, and increasing GST activity [2]. Phytochemicals are found to exert an antioxidant effect in the normal cell, while in cancer cells, phytochemicals tend to increase reactive species beyond the threshold level at which the survival adaptation of the cell is rendered futile. Dietary phytochemicals exert anticancer, chemopreventive, and chemosensitizing properties by generating excessive reactive species levels at which the oxidative stress inside the cell is so high that the cell becomes destined to die (Figure 1).
Figure 1. Role of oxidant–antioxidant levels in cancer cells and cancer cell death. Phytochemicals exert their anticancer property by targeting the redox status of cancer cells. They exert cytotoxic action by scavenging reactive species or generating reactive species burst inside the cells. Caspase-med-Apoptosis: Caspase-mediate Apoptosis; COX: Cyclooxygenase; Cyt-C: Cytochrome C; GGT: γ-Glutamyl Transpeptidase; GST: Glutathione S-Transferase; HDAC2: Histone Deacetylase; HIF: Hypoxia-Induced Factor; HO: Hemeoxygenase-1; LPO: Lipid Peroxidation; MDA: Malondialdehyde; MMP: Mitochondrial Metalloproteinase; NAF: Nutrient-deprivation Autophagy Factor-1; NRF-2: Nuclear Factor Erythroid 2–Related Factor 2; NF-κB: Nuclear Factor kappa-B; NQO1: NADPH Quinone Oxidoreductase; PI3K: Phosphoinositide 3-Kinase; QR: Quinone Reductase; RNS: Reactive Nitrogen Species; ROS: Reactive Oxygen Species.
Curcumin is a naturally occurring polyphenol found in the rhizome of turmeric (Curcuma longa). Curcumin can target multiple signaling molecules to exert its biological efficacy, such as antioxidant, antimicrobial, anti-inflammatory, anti-mutagenic, antimicrobial, and anticancerous properties [3]. Curcumin (diferuloylmethane) neutralizes ROS generated from chemical carcinogens by inducing GST (a phase II metabolizing enzyme) and Quinine reductase. Not only does Curcumin scavenge ROS by inducing ROS-scavenging enzymes such as GST, Hemeoxygenase-1, and redox-sensitive inducible enzyme, but Curcumin can also exploit ROS generation to kill cancer cells [4]. Curcumin is found to generate ROS beyond the threshold level to induce apoptosis by downregulating anti-apoptotic protein, NF-κB, and COX-2 and upregulating the activity of tumor suppressor p53 [5]. In colon cancer, Curcumin induces apoptosis by increasing the production of ROS, Ca2+, upregulating the expression of proapoptotic proteins (BAX, Cytochrome C, p53, and p21), Caspase 3, and reducing the mitochondrial membrane potential [1][6]. Moreover, Curcumin exerts its anticancerous activity by inhibiting proinflammatory enzymes such as inducible NOS (iNOS) and tumor necrosis factor-α (TNF-α). In addition, Curcumin can inhibit hypoxia-induced ROS in hepatic carcinoma cells (HCC) by downregulating the expression of hypoxia-inducible factor-1 (HIF-1) [7].
Another polyphenol, Resveratrol (3,5,4′-trihydroxy-trans-stilbene), belongs to the stilbenoids groups and comprises two phenol rings linked by an ethylene bridge. Resveratrol is commonly found in the skin and seeds of grapes and many other plant species. Resveratrol has several biological efficacies, including antioxidant and anticancer properties. It has been found that Resveratrol induces its anticancer efficacy by numerous mechanisms, including but not limited to the overproduction of reactive species. It has been found that Resveratrol suppresses the expression of NAF-1 by facilitating NRF-2 signaling and overproducing ROS in pancreatic cancer cells [8]. Moreover, in colon cancer cells, Resveratrol inhibits iNOS expression along with post-translational modification and translocation of NF-κB, resulting in the inhibition of inflammation associated with cancer cells [8].
Apigenin (4′,5′,7-trihydroxyflavone) is a flavone extracted from plants that are abundantly found in vegetables, fruits, medicinal plants, etc., that has shown its biological efficacy as an antioxidant, organ protector, and anticancer agent [9]. Apigenin was found to exert its anticancer properties through apoptosis, cell cycle arrest, immune response, and ROS. Administration of Apigenin (12.5–50 μM) in the papillary thyroid carcinoma cells leads to cell cycle arrest via inhibiting the expression of CDC25c and overproduction of ROS, which ultimately causes DNA damage [10]. Apigenin is also used as a ROS amplifier to enhance the cytotoxic effect of Metformin in vitro and in vivo. The combination of Metformin (5 μM) and Apigenin (20 μM) is found to induce ROS-dependent severe DNA damage and apoptosis in human pancreatic cells. Moreover, in vivo combination of Metformin (75 mg/kg b.w.) and Apigenin (5 mg/kg b.w.) is found to have a profound effect on tumor weight [11]. Quercetin (3′,3′,4′,5′,7 pentahydroxyflavone) belongs to the flavonol group and is abundant in nature and common to the human diet. Quercetin exhibits chemopreventive properties owing to its antioxidant properties. It has been observed that the presence of an OH group and double bonds in Quercetin has provided antioxidant capability to the Quercetin molecules. Quercetin can scavenge both ROS and RNS [12]. Zhang et al. [13] observed that the antioxidant properties of Quercetin (15) μM helps in enhancing the therapeutic efficacy of Paclitaxel (12.5 μM) against CaP by inducing endoplasmic reticulum stress and intracellular ROS leading to CaP cell cycle arrest and death. Moreover, Quercetin can form Quercetin radicals to scavenge peroxyl radicals. The formation of Quercetin radicals can overall increase the intracellular ROS level. Quercetin is also observed to induce free radical-mediated apoptosis by p38/ASK1/AMPKα1/COX-2 [14].
Rutin (3,3′,4′,5,7-pentahydroxyflavone-3-rhamnoglucoside) is a flavonol commonly found in passionflower, buckwheat tea, apple, and many other plants. Rutin prohibits liver cancer cell proliferation at the IC50 value of 52.7 μM/L and enhances cell death. Moreover, Rutin treatment significantly alters the expression of drug-metabolizing CYP3A4 and CYP1A1 and phase II reaction catalyzing enzyme NADPH Quinone oxidoreductase I (NQO1) and GST variant P1 [15]. In another study, the administration of Rutin is followed by a reduction in cell viability due to enhanced ROS generation and dose-dependent nuclear condensation in cervical cancer cells [16].
Caffeic acid (3,4-Dihydroxycinnamic acid) belongs to a subgroup of hydroxycinnamic acids of polyphenol groups and is believed to possess antioxidant properties that help in many biological activities [17]. Caffeic acid (0–500 μM) induces cell death in the colon and cervical cancer by inhibiting Histone Deacetylases (HDAC) 2. Furthermore, inhibition of HDAC2 leads to the overproduction of ROS, cell cycle arrest, and caspase-3-mediated apoptosis in the cancer cells [18]. Caffeic and Ferulic acid are found to chelate RNS and form stable intermediates with these reactive species [19]. The scavenging capacity of Ferulic acid (0–100 μM) facilitates cytoprotection by inhibiting DNA damage, inflammation, lipid peroxidation, and stimulating apoptosis [20]. Sinapic acid (3-(4-hydroxy-3,5-dimethoxyphenyl) prop-2-enoic acid) exhibits a chemopreventive effect on colon carcinogenesis. The authors observed that Sinapic acid (40 mg/kg b.w.) could decrease tumor prevalence, modulate LPO markers, and increase antioxidant defense by regulating phase I and II detoxifying enzymes [21]. In another study, Sinapic acid showed anticancer properties both in free and nano-capsulated form. It was observed that Sinapic acid (125.23 µM) showed an apparent increase in the ROS level in HeP-2 cells, leading to oxidative stress and a mitochondria-dependent pathway of apoptosis [22].
Table 1. Occurrence and anticancer mechanism of the phytochemicals.
Phytochemicals Found in Function Role in Redox Balance Ref.
Curcumin Turmeric Anticancer Induce Glutathione S-transferase, Quinine reductase, and Hemeoxygenase, induce apoptosis by upregulating the expression of ROS beyond a threshold level, Ca2+, BAX, Cyt C, p53, p2, Caspase 3 and reducing MMP, inhibit iNOS and TNF-α, HIF-1, hypoxia-induced ROS [4][5][6][7]
Resveratrol Grapes Anticancer Facilitate Nrf-2 expression, overproduction of ROS, suppresses NAF-1 and iNOS expression, and post-translation modification and translocation of NF-κB [8]
Apigenin Parsley, Chamomile, Celery, Vine-Spinach, Artichokes, and Oregano Organ protective and Anticancer Inhibiting the expression of Cdc25c, overproduction of ROS, DNA damage [9][10][11]
Quercetin Citrus fruits, Apples, Onions, Parsley, Sage, Tea, Red wine, Olive oil, Grapes, Cherries, Blueberries, Blackberries, and Bilberries Chemopreventive Scavenge ROS and RNS, enhance Paclitaxel efficacy, ER-stress and increase ROS beyond a threshold level, induce free radical-mediated apoptosis by p38/ASK1/AMPKα1/COX2. [12][13][14]
Rutin Passionflower, Buckwheat, Tea, and Apples Anticancer Alter the expression of CYP3A4 and CYP1A1, NQO1, and GST variant P1. Enhances ROS beyond threshold level and nuclear condensation [15][16]
Caffeic acid Coffee, Red wine, Berries, and Apples Anticancer Inhibit HDAC2, overproduction of ROS, cell cycle arrest, Caspase-3-mediated apoptosis [18]
Ferulic acid Rice, Wheat, Oats, Pineapple, Grasses, Grains, Beans, Coffee Beans, Artichokes, and Peanuts Cytoprotective Scavenge ROS, inhibit DNA damage, inflammation, LPO, stimulate apoptosis [20]
Sinapic acid Spices, Citrus, Berries, Fruits, Vegetables, Cereals, and Oilseed crops Chemopreventive Decrease tumor prevalence, modulate LPO markers, increase phase I and phase II detoxifying enzymes. Increase ROS, oxidative stress, mitochondrial-dependent apoptosis [21][22]
Gallic acid Hazel, Tea Leaves, and Oak Barks Anticancer Increases ROS, decreases GSH, MMP loss, activates p53, facilitates JNK-mediated apoptosis [23]
Betulinic acid Birch, Eucalyptus, and Plane trees Anticancer Neutralizes ROS, upregulates GST, γ-glutamyl transpeptidase, and DT-diaphorase, reduces MDA levels [24]
Lupeol White cabbage, Green pepper, Strawberry, Olive, Mangoes, and Grapes Anticancer Excessive ROS generation, apoptosis, downregulation of m-TOR/PI3K/AKT axis, loss of MMP [25]
Capsaicin Chilli pepper, Oregano, Cinnamon, and Cilantro Carcinogenic Increase tumoral load and prevalence, histone modification by HDAC and TLR4 dysregulation [26][27]
Cycasin Cycad nuts Carcinogenic Promotes neoplasia [28]
β-myrcene Verbane, Lemongrass, Bay, Rosemary, Basil, Cardamom Carcinogenic Promote adenomas and carcinoma  
Alkylbenzenes Artemisia dranunculus, Nutmeg Carcinogenic Form DNA adducts, micronuclei, malignant tumors [29]
Coumarin Cinnamon, Tonka Beans, and Sweet Clover. Carcinogenic Adenomas and carcinomas  
Safrole and Methyleugenol Artemisia dranunculus, Nutmeg Carcinogenic Genotoxicity, mutagenicity, chromosomal aberrations [30][31]
Aristocholic acid Birthworts or pipevines and Asarum Carcinogenic DNA damage, DNA adduct, premalignant alterations [31]
Isothiocyanates Cruciferous, Watercress, and Radish Carcinogenic Papillary of nodular hyperplasia and carcinoma [32]
Gallic acid (3,4,5-trihydroxybenzoic acid) is grouped with phenolic acid and found in hazel, tea leaves, oak barks, etc. Gallic acid (0–50 μM & 100–200 μM) induces lung cancer apoptosis by increasing ROS levels and decreasing GSH levels, leading to the loss of mitochondrial membrane potential. Moreover, Gallic acid-induced ROS at 50 g/mL facilitates c-Jun-NH2 kinase (JNK) mediate apoptosis in lung fibroblast cells. Formation and accumulation of H2O2 lead to the activation of the p53 pathway and JNK pathway, culminating in apoptosis [23]. Furthermore, Gallic acid exerts anticancer properties against CaP, leukemia, esophageal cancer, and cervical cancer through the ROS burst and antioxidant defense system [23].
Terpenoids or isoprenoids are diverse phytochemicals showing various biological efficacy, including chemopreventive and chemosensitizing effects in in vitro, preclinical, and clinical settings. Betulinic acid (3β-hydroxy-lup-20 (29)-en-28-oic acid) shows a chemopreventive effect by modulating xenobiotic and antioxidative enzyme activities. Betulinic acid (10 mg/kg b.w.) has been observed to easily neutralize the reactive species by upregulating the activity of phase II enzymes such as GST, γ-Glutamyl transpeptidase, and DT-diaphorase and reducing MDA levels [24]. Moreover, Betulinic acid interacts with xenobiotic metabolizing enzymes to prevent the development of skin papilloma and carcinomas in DMBA (10 mg/kg b.w.)-treated groups [24]. Another triterpene, Lupeol, exhibits anticancer potential against human lung carcinoma cells by excessive ROS generation, apoptosis, and downregulation of the mTOR/PI3K/AKT axis. Moreover, it has been observed that the cytotoxic potential of Lupeol was governed by the loss of MMP, which further leads to higher ROS levels and apoptosis [25]. The phytochemicals and their role in anticancer therapy by perturbing redox homeostasis of the cancer cells can be exploited extensively as one of the important benefits of using natural compounds is few to no side effects in normal cells.

2. Toxic Effect of Phytochemicals

More than 10,000 plant metabolites have been identified to date; however, the toxicological characterization of many of these secondary metabolites is not yet preclinically and clinically defined. Another challenge in phytochemical research is the contradictory effects reported in different setups. The contradictory effects of phytochemicals might be dose/concentration related. The different doses might elicit different effects. Few phytochemicals have anticancer properties and show chemopreventive activity when applied in different setups. For instance, Capsaicin acts as a co-carcinogen with DMBA/TPA to induce skin cancer. Applying phytochemicals such as Capsaicin on the dorsal skin of a DMBA-initiated TPA-promoted skin cancer model increases the number, size, and amount of cancer [26]. A recent study showed that continuous exposure of low dose Capsaicin facilitates colorectal cancer progression by further promoting abnormal expression of HDAC and histone modification leading to dysregulation of Toll-like receptor 4 (TLR4) [27].
Another phytochemical, Cycasin (methylazoxymethanol-D-glucoside), commonly found in cycad nuts, was reported to have carcinogenic properties. It was observed that Cycasin and its metabolite, Methylazoxymethanol, promotes neoplasia in the liver, kidneys, and intestines, which prompted the international agency of research on cancer to identify Cycasin and its metabolite as a carcinogen to humans [28]. Furthermore, oral administration of Acyclic monoterpene, β-myrcene (1000 mg/kg b.w.), which is commonly found in verbena, lemongrass, bay, rosemary, basil, cardamom, etc., proliferates liver and kidney (adenomas and carcinomas) cancer [28].
Alkylbenzenes such as Asarones, Elmicin, Estragole, and Safrole, found in essential oils or parts of the Aristolochiaceae plants, Artemisia dracunculus, nutmegs, are reported to have carcinogenic properties by forming DNA adducts, micronuclei, and malignant tumors. Moreover, benzopyrene, such as Coumarin, increases the incidence of renal tubule adenomas, alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinoma, HCC, etc. [29]. Moreover, rodent studies have demonstrated that Safrole and methyleugenol act as hepatocarcinogens. In silico data also report that Myristicin might play a role in carcinogenesis, but studies specify that 2 mM/kg/day of Myristicin for 2 years would lead to a significant but weak increase in hepatic tumor burden. However, conclusive evaluation or data regarding the carcinogenic properties of Myristicin does not exist [30]. Safrole, methyleugenol, and betel quid are further implicated in increased HCC risk, genotoxicity, mutagenicity, and chromosomal aberrations [31].
Aristocholic acid or herbs containing Aristocholic acid are reported to promote HCC both in vitro and in vivo. Aristocholic acid increases HCC incidence of DNA damage, DNA adduct, and premalignant alterations in mice and canines. Moreover, Gingko biloba extracts increase the incidence of HCC, hepatocellular necrosis, and hepatoblastoma [31]. Hirose et al. [32] reported the cancer-promoting properties of isothiocyanates. Their study observed that Benzyl isothiocyanates and Phenylethyl isothiocyanates (0.1% of diet) could increase the incidences of papillary nodular hyperplasia and carcinoma in the urinary bladder of the DEN and N-butyl-N-(4hydroxybutyl) nitrosamine-treated rat model. However, several reports have also shown the anticancer activity of the isothiocyanates, suggesting that the dose [33], duration of treatment, or any other circumstance might play the defining role of a phytochemical as a carcinogen, co-carcinogen, or anti-carcinogen (Table 2).
Table 2. Anticancer and carcinogenic effect of phytochemicals doses and toxicity models used.
Phytochemical Doses Effect Models Ref.
Curcumin 2% w/v for 30 days Scavenges ROS and induce scavenging enzymes Male mice [4]
1 kg/day for 2 days Inhibited NF-kB HCT116 xenograft in nude mice [5]
5–75 μM, for 6–72 h Inhibited COX-2 HT-29 cells [5]
60 μM Inhibit p53 phosphorylation Colon Cancer cells [5]
0, 5, 10, 20 and 50 μM for various time periods. Increase ROS, Ca2+, BAX, Cytochrome C, p53, and p21, Caspase 3, and reduce MMP Colo-205 colon cancer cells  
Resveratrol 50 μM for 24 h Suppress NAF-1 and upregulate Nrf-2, ROS Human pancreatic cancer cell lines Panc-1, Mia paca-2, CF pac-1, and BxPC-3 [8]
Apigenin 12.5–50 μM Overproduction of ROS, genotoxicity, and cell cycle arrest Papillary thyroid carcinoma cells [10]
(20 μM with 10 μM Metformin) or (5 mg/kg b.w with 75 mg/kg b.w. Metformin) ROS-dependent DNA damage and antioxidant Human pancreatic cells and mice [11]
Quercetin 15 μM with 12.5 μM Paclitaxel ER stress and ROS-induced DNA damage Prostate cancer cell line [13]
0–400 μM Increased ROS Breast cancer, MCF-7 [14]
Rutin 0–100 μM Increase antioxidant status Liver cancer, HEPG2 [15][16]
60–100 μM ROS-generation Cervical cancer, HPV-C33A  
Caffeic acid 0–500 μM HDAC inhibtion and ROS generation Cervical cancer (HeLa and SiHa) and colon cancer (HCT-116 and HCT-15) [18]
Ferulic acid 0–100 μM Inhibit DNA and lipid damage Cytoprotective [20]
Sinapic acid 40 mg/kg b.w. Modulate LPO markers and increase antioxidant enzyme Mice [21]
125.23 μM Increase in ROS level HeP-2 cells [22]
Gallic acid 0–200 μM; 50 g/ml Increase in ROS level Lung cancer, Calu-6 and A549 [23]
Betulinic acid 10 mg/kg b.w. Upregulate phase II antioxidant enzyme Mice [24]
Lupeol 12.5–50 μM Increased ROS generation Lung cancer, A427 [25]
Capsaicin 10 mg/kg b.w. Promoted cancer Female mice [26]
10 mg/kg b.w. Promoted cancer Male Wistar rate
Cycasin 50–75 mg/kg b.w. for 5 days Promoted cancer Monkey [28]
β-myrcene 1000 mg/kg b.w. for 5 days/week Promoted cancer Mice  
Coumarin 200 mg/kg b.w. Promoted cancer Mice [29]
Safrole and Methyleugenol 5000 mg/kg b.w.; 0.05 μM/b.w. Promoted cancer Mice [30][31]
Aristocholic acid 5 mg/kg b.w. for 3 weeks Promoted cancer Mice [31]
Gingko biloba
extract		 0–1000 mg/kg b.w., 5 days per week for 14 weeks. Promoted Cancer Mice [31]
Isothiocyanates 0.1% of diet Promoted cancer Mice [32]
Annexin A2-conjugated curcumin loaded PLGA nanoparticles. 0–80 µM Inhibit angiogenesis and cancer cell survival Breast cancer cell lines [34]
Resveratrol-loaded nanoparticles 100–300 µM Inhibit metastasis and regulate redox homeostasis Mice [35]
DMSA conjugated Apigenin nanoparticles 0–16 µg/mL;
5 mg/kg b.w.		 Increased bioavailability and anticancer effect Lung cancer, B16F10 and A549; Mice [36]
Quercetin loaded chitosan nanoparticles 12.5–200 μM;
25 mg/kg b.w.		 Reduce tumor volume and increase the antioxidant level Lung cancer, A549; breast cancer, MDA MB 468; Mice [37]
Nanoemulsion of Rutin 30–300 μM;
20–300 μM;
50–300 μM		 Increased bioavailability and anticancer effect Lung cancer, A549;
Colon cancer, Caco-2 human fibroblast cells, respectively		 [38]
Rutin loaded-PCL-PEG and PLGA nanoparticles 5–50 mg/kg b.w. Suppress oxidative stress Rat [39]
Rutin loaded PCL-PEG nanoparticles 0–60 μM Suppress oxidative stress Human ovarian cancer, Skov3 [40]
Betulinic acid loaded PLGA nanoparticles 10–80 µg/mL;
100 mg/kg b.w.		 Balance redox homeostasis Hep-G2 cells; Wistar rats

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Subjects: Biology; Biochemistry & Molecular Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Homa Fatma
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Mohd Jameel
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Hifzur R. Siddique
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Update Date: 24 Apr 2023
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