Combating oxidative stress disorders with citrus flavonoid: Naringenin

Life Sciences 208 (2018) 111–122

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Combating oxidative stress disorders with citrus flavonoid: Naringenin ⁎

T

Nurul Hannim Zaidun, Zar Chi Thent, Azian Abd Latiff Discipline of Anatomy, Faculty of Medicine, Universiti Teknologi MARA, Selangor, Malaysia

A R T I C LE I N FO

A B S T R A C T

Keywords: Naringenin Antioxidants Oxidative stress disorders Alternative medicine

The incidence of diseases related to oxidative stress disorders have been increased dramatically. Alternatives medicine or the active compound extracted from the natural products received great attention among researches at the present era. Naringenin (NG), a common dietary flavanone, found in the citrus fruits such as oranges, bergamots, lemons and grapefruit. It is used in the several oxidative stress disorders as the nutraceutical value of the compound emerges. Functionally, the antioxidants effect of NG is primarily attributed by reducing the free radical like reactive oxygen species (ROS) and enhancing the antioxidants activity such as superoxide dismutase (SOD), catalase, glutathione (GSH) in chronic diseases such as cardiovascular, neurodegenerative, diabetes, pulmonary, cancer and nephropathy. The present review article summarised the antioxidant property of NG and its molecular mechanism towards such diseases. Pubmed, Science Direct, Scopus, Web of Science and Google scholar were searched using the terms ‘naringenin’, ‘oxidative stress disorders’, ‘naringenin and cardiovascular diseases’, ‘naringenin and diabetes mellitus’, ‘naringenin and neurodegenerative diseases’, ‘naringenin and pulmonary diseases’, ‘naringenin and cancer’ and ‘naringenin and nephropathy’. There has been special attention on evaluating anti-oxidative effect of NG on neurodegenerative diseases. Although some mechanisms of action remain vague, the current review highlighted the potential use of NG as a oxidative stress reliever which can be used as next prophylaxis compound in the treatment of the various oxidative stress disorders.

1. Introduction Oxidative stress a condition of over production of free radicals and oxidants in the body leading to counteract the homeostasis and subsequently causing serious imbalance [1, 2]. It arises from various sources of disease state or lifestyle such as episodes of ketosis or chronic hyperglycaemia, sleep restriction, and excessive nutrient intake [3]. The imbalance between oxidants and antioxidants damage the proteins, lipids and DNA which in turn cause physiological dysfunction of the cells and cell death [4]. Oxidative stress is considered as the biggest contributor in the pathogenesis of diabetes mellitus, cardiovascular disease, neurodegenerative disease like Parkinsonism and Alzheimer [5–8], and obstructive lungs disease [9]. Being the co-factor to multiple diseases, oxidative stress is an attractive candidate target for therapy. According to the literatures, different race shows different levels of oxidative stress. It was observed that Japanese in US have high level of oxidative stress markers than Caucasian [8]. In term of the trend of the dietary intake, vegetarians have low risk of developing oxidative stress diseases. On the other hand, non-vegetarians have high risk of having oxidative stress diseases. Therefore, modern researches have recommended to

⁎

alter the diet in order to prevent such diseases [9]. In Malaysia, disease related to oxidative stress like diabetes mellitus are increasing up to 20.8% from 2006 to 2011 [10]. Diseases related to neurodegeneration are increasing alarmingly and expected to have 39,000 new cases in 2020 [11]. Over the decades, several alternative medicines or herbs from natural products were studied to observe the therapeutic effects. The potential effect of certain crude extracts, such as Momordica charantia, Piper sarmentosum, Piper betel, etc. were observed in few clinical studies [10, 11]. Several positive effects of the extracts or active compound on the oxidative stress disorders were also proved [10–12]. Lately, the studies on active compounds against several diseases have attracted the researchers as the therapeutic effect of the definite compound from the extract is gradually revealed from the findings [12]. Many compounds from the folk medicines were isolated and investigated to observe their potential effects. Several experimental and clinical studies on polyphenols, flavanones, flavonoids and isoflavones were also conducted in recent years. Among them, Naringenin is a potential flavone to be emphasized. Naringenin, is an active compound from flavonoids family, present in many citrus based fruits especially grapefruits. Its anti-oxidative property was widely studied and proven to be beneficial in

Corresponding author at: Discipline of Anatomy, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Selangor, Malaysia. E-mail address: azianabdullatiff@gmail.com (A.A. Latiff).

https://doi.org/10.1016/j.lfs.2018.07.017 Received 6 June 2018; Received in revised form 5 July 2018; Accepted 10 July 2018 0024-3205/ © 2018 Published by Elsevier Inc.

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oxidative stress diseases [12–15]. However, the overall antioxidant effect of Naringenin on various oxidative stress disorders was not summarised in detail. In the present article, we reviewed and summarised the available literatures on the anti-oxidative effect of Naringenin and on how it acts as oxidative reliever in numerous oxidative stress diseases. 2. Oxidative stress disease When cell uses oxygen to create energy in term of ATP, free radicals are generated consequently. These by-products are generally known as reactive oxygen species (ROS) or reactive nitrogen species (RNS) that result from the cellular redox (reduction-oxidation) process [1]. When there are more free radicals and oxidants being produced in the body due to some on-going pathology, the excess free radicals disturb the normal body process which results in oxidant and antioxidant imbalance and eventually cause oxidative stress. Free radicals are produced endogenously or exogenously. Endogenous free radicals, ROS and RNS, come from many sources such as during irradiation by UV light, X-rays, and gamma-rays. It can be produced in the metal-catalyzed reactions, by neutrophils and macrophages during the inflammatory process. Exogenous free radicals represent as pollutants in the atmosphere. It is noted that ROS and RNS are the by-products of mitochondria-catalyzed electron transport reactions and other mechanisms [16]. The mechanism on how the oxidants causes damage is by stimulation of the cell proliferation in which rise in free calcium and proteins increased the transition metal ions that used to catalyse the free radicals, bind the protein DNA and destroy them. Eventually, it triggers the apoptosis and cause oxidative damage [2]. Endogenous oxidative enzymes such as NADPH oxidase, xanthine oxidase, or the mitochondrial respiratory chain is opposed by its anti-oxidative enzymes like superoxide dismutase, glutathione peroxidase, heme oxygenase, thioredoxin peroxidase/peroxiredoxin, catalase, and paraoxonase [17]. Mitochondria are the major site responsible for more than 90% of the ROS generation [18]. During imbalance redox reaction, interleukins and inflammatory mediators are produced. Therefore, inflammation is one of the manifestations of oxidative stress and the common factor for condition like type 2 diabetes mellitus and cardiovascular disease. The pro-inflammatory state is caused by over generation of free radicals in oxidative stress related diseases such as atherosclerosis and cancer [19]. This hypothesis was agreed upon by the other group of researchers who showed that inflammation following the oxidative stress is induced by the glucose and free fatty acid (FFA). This type of inflammation have cumulative and independent effects which can be reversed by antioxidants [19].Oxidative stress is important from a biomedical point of view because it is related to a wide variety of human diseases, such as neurodegenerative disease (e.g., Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis), inflammatory disease (e.g., rheumatoid arthritis), cardiovascular disease (e.g., muscular dystrophy), allergies, immune system dysfunctions, diabetes, aging and cancer [20]. The overall information on the mechanism of oxidative stress and its related diseases were summarised as schematic diagram in Fig. 1.

Fig. 1. Chemical structure of Naringenin [21, 22].

ethnicity and habitation [23]. Naringenin is rich in Mediterranean diet as their diet mainly relies on fruits and vegetables based food [24]. In an experimental animal study, Naringenin is proven to have multiple therapeutics properties. It is believed to have antithrombotic [25], anti-atherosclerosis [26], antidiabetic [27], antihypertension [28], anti-inflammatory [29] and anti-hyperlipidaemic [30] properties. However, one of the properties that is well studied is its anti-oxidative effect [13–15]. The benefits of Naringenin are attributed to its antioxidant, radical scavenging and metal chelation, enzyme activity regulation and gene expression regulation [31, 32]. Naringenin is introduced into the body as Naringin, the glyucoside form of the Naringenin. It is usually bound to a glucose moiety which affecting its bioavailability [33, 34]. Once absorbed, Naringin is deglycosylated by gastrointestinal bacteria forming Naringenin. It then metabolized to form phenolic acids, p-hydroxyphenylpropionic acid (PHPP) and p-hydroxybenzoic acid (PHB) [14]. Naringenin can be found in the plasma, urine faeces and bile via different mechanism. The major content of Naringenin glucuronide in urine indicates that the conjugation is either from the liver or intestine. The compound is metabolized by the bile as enterohepatic recycling of the compound. In the plasma, Naringenin has been detected but not more than 4 μmol. Because of its lipophilic nature, Naringenin concentration is thought to be higher in the tissue than plasma [12]. Therefore, the bioavailability of Naringenin is less than it is anticipated. A study reported that only 4% bioavailability is achieved in an experiment on rabbit via oral administration [35]. It is suggested that NG is better to be in capsular form where the effective volume can be achieved [36]. Apart from being highly anti-oxidative, Naringenin has broad window of toxicity. It has LD50 values of 600 mg/kg body weight where 0% mortality was found at doses 100 mg/kg body weight and 100% mortality was found in the dose of 2000 mg/kg body weight [13]. Data on Naringenin intake being used as single therapeutic agent is not widely available. However, flavonoids as a whole, has long been used non-specifically in traditional medicine in Asian countries. According to the reports on the meta-analysis study in Asian population, the people who take flavonoids frequently in their diet has less number of breast and prostate cancers cases compared to the Western countries [37]. There is also an evident that Hawaiian population who takes apples and white grapefruits to form large part of their diet, has less number of lung cancer cases [36]. Other epidemiological studies also observed an inverse association between consumption of some nutritional flavonoids and the risk of human cancers at many sites [24]. Epidemiologically it was reported that Western-style diet is the major key driver to the development of cardiovascular event, hypercholesterolemia and hyperglycaemia. Consumption of fruits and vegetable enriched with citrus flavonoids showed positive impact on the metabolic syndrome including hypertension, atherosclerosis, obesity and diabetes mellitus. Generally, the active compound in the dietary sources is beneficial for the treatment of such chronic oxidative stress diseases [32]. The anti-oxidative effect of NG was summarised in Table 1.

3. Naringenin Naringenin is an active compound which was first discovered by Power and Tutin as chalcone in 1907. Its formulation was then improvised by Dean in 1963 [21]. It is a flavanone glycoside which has a molecular formula of C27H32O14 and molecular weight of 580.4 g/mol (Fig. 2). It highly enriched in citrus fruits such as grapefruits and lemon. Even though the recommended daily intake of Naringenin or flavonoids is not available at this present time, the estimated daily intake of flavonoid among US population is 1 g/day according to a study done by Kuhnau [22]. However, the latest finding on flavonoids intake showed that the daily intake of flavonoids including Naringenin depends on the 112

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Fig. 2. Schematic diagram showing the mechanism of oxidative stress in developing various disease.

4. Naringenin and oxidative stress disorders

mechanism for many CVD risk factors, which additionally supports its central role in CVD [38]. Naringenin serves as an atherosclerotic agent in CVD. Multiple animal studies have shown that CVD occurred due to oxidant-antioxidant imbalance that promotes the atherosclerotic plaque formation. Naringenin improves lipid profile, increase co-oxidation of NADH; suppresses inflammatory cytokines and reduces foam cell formation; prompts cell cycle arrest in vascular smooth muscle cells (VSMC) and down regulate atherosclerosis related genes [41] that involved in the atherosclerosis. NG also responsible to protect the cardiac injury in oxidative stress disorder and restore the normal histological architecture of cardiac tissue [31]. The detailed mechanism of NG improving the cardiac tissue morphology is still unknown. In cardiac fibrosis, NG modulates p38 and PKC-β protein expression possibly through its known antioxidant actions and reduced the disease progression [42]. Eventually, NG proved that it has anti-atherosclerosis and cardioprotective effects which are mainly achieved from its own antioxidant property. The summarise literature on NG towards cardiovascular diseases paved the way for future research.

4.1. Naringenin and cardiovascular disease Studies have proved that most of the cardiovascular diseases (CVD) resulted from the complications of atherosclerosis38. In the early stage of atherosclerosis, endothelial dysfunction can be detected earlier than it is evident by radiological assessment [17] (angiography or ultrasound evidence of structural coronary artery disease). Endothelial dysfunction resulted from oxidative stress promotes atherogenesis by reducing the Nitric oxide (NO). As a key regulator of endothelial function, vascular NO produced from the endothelial cells, relaxes the blood vessels, prevents platelet aggregation and adhesion, limits oxidation of lowdensity lipoprotein (LDL) cholesterol, inhibits proliferation of vascular smooth muscle cells, and decreases the expression of pro-inflammatory genes that advance atherogenesis [38]. However, in the state of oxidative stress, peroxynitrite is produced from the endothelial cell. Peroxynitrite (ONOO) is a reactive nitrogen species which causes direct structural damage and accelerates the atherosclerotic process [17, 39]. Increase in ROS production mediates various signalling pathways that lead to the vascular inflammation in atherogenesis. As a consequence, from vascular inflammation, oxidised LDL influences the consequences of the atheromatous plaque by increasing the intracellular level of calcium influx [30]. Endothelial dysfunction results from macrophage accumulation via oxidising the LDL receptors. This oxidised-LDL promotes more uptake of LDL to the macrophages. Enhanced LDL uptake by macrophage leads to the foam cells formation which deposits in the tunica intima of the arterial wall [40]. Consequently, fatty streak is formed in the endothelial lining of the arterial wall and develops atherosclerosis. A vicious cycle of oxidative stress-mediated inflammation and inflammation-induced oxidative stress worsens the cardiovascular complications [31]. Earlier experiment on oxidative stress observed that ROS is a causative factor in atherosclerosis and its related cardiovascular disease (CVD). Oxidative stress is the unifying

4.2. Naringenin and diabetes mellitus Evidence suggested that oxidative stress plays a role in the pathogenesis of diabetes mellitus and its complications is increasing alarmingly. Hyperglycaemia aggravates oxidative stress reaction by blunting the anti-oxidative mechanism [4]. Oxidative stress in diabetes occurs due to the overproduction of the superoxide in mitochondria [43] causing the increased influx of glucose via polyol pathway, increased intracellular formation of advanced glycation end products (AGEs), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C isoforms, and overactivity of the hexosamine pathway. This will further cause insulin resistance and glucose intolerance and accelerate the diabetic complications [43]. An earlier study demonstrated that hyperglycaemia-induced superoxide 113

In vivo

In vivo

In vivo

In vivo

In vivo

3.

4.

5.

6.

7.

Drug-induced (Isoproterenol) cardiotoxic rat model

Cardiac hypertrophy induced rat model

114

Both In vivo and in vitro

In vivo

10.

11.

NG

Type 2 DM rat model and cell line

45 adult male Wistar rats 40 male albino Wistar rats

NG

42 Male albino rats

39 male and female Swiss albino inbred mice 63 male Sprague–Dawley rats and Human umbilical vein endothelial cells (HUVECs)

70 male and female CBA inbred

64 male albino Wistar rats

60 male C57BL/6 mice

40 male Swiss albino rats

42 male Swiss albino mice

60 male Wistar rats

Male Sprague-Dawley rats

40 male Wister rats

Study designs/sample size

NG

Retina of streptozotocin-induced diabetic Mangiferin and NG rats

NG

NG

NG

NG

Alloxan-induced diabetic mice

Naringenin and neurodegenerative disease 11. In vivo ß-amyloid-induced Alzheimer disease model 12. In vivo Streptozotocin-induced neuronal injury Alzheimer's disease rat model

In vivo

Naringenin and diabetes mellitus 8. In vivo Alloxan-induced diabetic mice

9.

NG

Drug-induced (Doxorubicin) cardiac toxic NG rat model

Hypoxia-induced murine model

Type 1 DM rat model

NG

NG

Type 1 diabetic rat model

In vivo

2.

Single/ synergistic effect

NG

Study model/subject

Naringenin and cardiovascular disease 1. In vivo High cholesterol diet rat model

No. Type of study

Table 1 Summarised experimental and molecular findings on the potential antioxidants effect of Naringenin.

Single dose, pretreatment 2 weeks

5 weeks

6 weeks (in vivo) and 30 mins (in vitro)

7 day

7 days

8 weeks

7 weeks

7 days

Single dose posttreatment

10 weeks

8 weeks days

90 days

Duration of study

Finding/result

50 mg/kg, orally

100 mg/kg, orally

NG 50 mg/kg daily, orally

50 mg/kg/bw, intraperitoneally 50 mg/kg/bw, intraperitoneally 50 and 100 mg/kg/bw, orally (in vivo) and 3 or 30 μM (in vitro)

[61]

[103]

[54]

[52]

[51]

[102]

[101]

[100]

[99]

[50]

[42]

[31]

Ref

(continued on next page)

Reduced oxidative stress markers: 4-hydroxynonenal [64] (4-HNE), MDA, thiobarbituric reactive substances (TBARS), hydrogen peroxide (H2O2), protein carbonyl (PC), reduced glutathione (GSH) in the hippocampus Increase antioxidant level: glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-Stransferase (GST), superoxide dismutase (SOD), catalase (CAT) and Na+/K+-ATPase in the hippocampus

Lowered hippocampal MDA content

Showed protective effects against alloxan-induced DNA-damage in peripheral lymphocytes. Decreased lipid peroxidation level in liver and kidney tissue Decreased blood glucose, serum lipid, MDA, ICAM-1, insulin resistance index and increased SOD activity (in vivo) Inhibited NF-κB activation and ICAM-1 mRNA expression in PA-treated endothelial cells (in vitro) Decreased level of TBARs and increased level of GSH. Moreover, increased levels of neuroprotective factors (Brain derived neurotrophic factor (BDNF)), tropomyosin related kinase B (TrkB) and synaptophysin in diabetic retina. In addition, reduced apoptosis regulatory proteins; B cell lymphoma 2 (Bcl2), Bcl-2 associated X protein (Bax) and caspase-3 found in the diabetic retina.

Reduced NO level protein and lipid oxidative markers; increased levels of enzymatic and non-enzymatic antioxidants; reduced myocardial reactive oxygen species (ROS) and nuclear DNA damage. 50 mg/kg/bw, orally Ameliorated myocardial fibrosis by modulating p38 and PKC-β protein expression. 5–10 mg/kg/bw, orally Increased tissue MDA; increased SOD, CAT reduced GLUT enzyme activities in the diabetic kidney; reduced apoptosis activity and in expression of TGF-β1 10 mg/kg/bw, orally Reduced the expression of hypoxia inducible factor 1a (HIF1a), vascular endothelial growth factor (VEGF), active caspase 3 and ubiquitin 25 mg/kg/bw, orally Reduced MDA; increased enzymatic and nonenzymatic antioxidant; reduced total NO content in heart tissue 100 mg/kg/bw, intraperitoneal Attenuated cardiac hypertrophy and interstitial fibrosis; improved left ventricular function in pressureoverloaded mice. 10, 20 and 40 mg/kg/bw orally Improved membrane bound enzymes and glycoproteins levels

50 mg/kg/bw, orally

Dose

N.H. Zaidun et al.

Life Sciences 208 (2018) 111–122

In vivo

In vitro

Both in vitro and in vivo

In vitro

In vivo

In vitro and in vivo

18.

19.

20.

115

21.

22.

NG

In vivo

25.

Allergen-induced (ovalbumin) chronic asthma model

NG

NG + hesperetin

In vivo

24.

House dust mite (HDM)-induced asthmatic model

NG

Naringenin and pulmonary disease 23. In vivo Allergen-induced(ovalbumin) asthma model

NG Cortical neuron cells isolated from the brains of neonatal rats (in vitro) and middle cerebral artery occlusion (MCAO) model (in vivo)

Epilepsy induced mice

Female BALB/c mice

40 male BALB/c mice

15 BALB/c mice

Sprague-Dawley rats

Single dose

4 week

24 days

Not available

15 days

50 mg/kg/bw intraperitoneal

Beverage: NG (9 mg: 100mls)

0.8 mg/kg/bw orally

Not available

40 mg/kg b.w

50, 100, 200 μM

Human keratinocyte cell line (HaCaT) Adult Swiss albino mice

48 h

NG

24 h (in vitro) and 1–3 h (in vivo)

Not available

VANL-100 (NG combined with Lipoic Acid)

Neurons isolated from the brains of rats (in vitro) and brain tissue of the rats (in vivo)

Pemphigus vulgaris (PV) treated keratinocytes

2 × 10−2 μmol/L(in vitro) and 1 × 10−4 mg/kg (in vivo)

24 h

20, 40 and 80 μM

NG(50 mg/kg), cucumin (200 mg/kg) and quercetin (50 mg/kg)

Neurons from Sprague-Dawley

16 days

Finding/result

[110]

[109]

[108]

[107]

[106]

[105]

[104]

[67]

Ref

(continued on next page)

[73] Reduced eosinophilic airway inflammation, airway hyper-reactivity and Th2 cytokine production from CD4 T cells Histopathological examination showed no goblet cells [74] metaplasia, decereased intra-alveolar macrophages; decreased subepithelial fibrosis, smooth muscle hypertrophy in airways, and lung atelectasis Reduced total serum IgE and of T helper 2 (Th2) [75] cytokines in the bronchoalveolar lavage fluid (BALF)

[111] Decrease in lipid peroxidation, increased GSH level and all the antioxidant enzymes. Decrease in seizure severity and improved in neuronal damage Inhibited apoptosis and oxidative stress, and regulated [112] the localization of Nrf2 protein

Improved memory and inhibited LPO and AChE activity, improved endogenous antioxidant enzyme activities, stimulated holinergic and serotonergic neurotransmission. It possesses potent antioxidant and cognitive enhancing properties Reduced level of ROS, improved mitochondrial dysfunction, by increasing high-energy phosphates level, mitochondrial ANT transport activity and the expression of Nrf2. Increased the free radical scavenging capacity in neuron cells and reduced infarct volume in middle cerebral artery occlusion (MCAO) followed by reperfusion Increased the activity of SOD, GSH-Px and TAC

Improved oxidative stress status by decreasing MDA and increasing glutathione content 20, 40 and 80 mM (in vitro) Activated Nrf2/ARE pathway in dopaminergic in vitro 70 mg/kg, orally (in vivo) Up regulated protein levels of Nrf2/ARE genes in vivo Reduced striatal oxidative stress and subsequent apoptotic signalling cascades in striatum in vivo Doses of 25, 50, or 100 mg/kg/ Decreased hippocampal MDA and improved SOD, day, orally catalase, and GSH. It reduced the hippocampal NF-κB, toll-like receptor 4 (TLR4), TNFα, COX2, iNOS, glial fibrillary acidic protein (GFAP) level and elevate nuclear factor (erythroid-derived 2)-like 2 (Nrf2) Unable to extract the dosage Counteracted MPTP-induced dopaminergic information degeneration by regulating SYN pathology, neuroinflammation, and oxidative stress

50 mg/kg, orally

Dose

NG

30 adult male Albino Wistar rats

5 days

7 days

2 h (in vitro) 4 days (in vivo)

11 days

Duration of study

Neurons isolated from the brains of rats

NG+ cucumin +quercetin

C57BL/6J mouse model

17.

1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP)-induced αsynuclein (SYN) pathology and neuroinflammation Oxidative stress induced rats

NG

In vivo

16.

Male albino Wistar rats (n = 72)

In vivo

15.

NG

SH-SY5Y cells/mice

NG

Drug-induced [6-hydroxydopamine (6OHDA)]- neurotoxicity in models of Parkinson's disease model.

Both in vitro and in vivo

14.

Lipopolysaccharide (LPS)-induced cognitive decline in rats

15–20 male albino Wister rats

NG + Hesperitin

Drug-induced (rotenone) Parkinsonism

In vivo

Study designs/sample size

13.

Single/ synergistic effect

Study model/subject

No. Type of study

Table 1 (continued)

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Smoke exposure-induced rat model

26.

In vivo

31.

116

In vivo

35.

Drug(cisplatin)-induced nephrotoxicity rat model

NG

NG

Drug-induced (gentamycin) nephrotoxicity

In vivo

34.

NG

NG

NG

NG

1,2-dimethyhydrazine (DMH)-induced precancerous lesions in colon

N-nitrosodi ethylamine (NDEA)-induced hepatocarcinogenesis

Benzo(a)pyrene-induced pulmonary carcinogenesis

Cancer cells

Naringenin and nephropathy 33. In vivo Drug-induced (daunorubicin (DNR)) nephrotoxicity rat model

In vivo

In vivo

30.

32.

In vitro

29.

NG

NG

In vitro

28.

Cancer cells

NG

NG

Single/ synergistic effect

Naringenin and cancer 27. In vitro Cancer cells

In vivo

Study model/subject

No. Type of study

Table 1 (continued)

24 Male Wistar albino rats

28 male Sprague-Dawley rats

18 male Sprague–Dawley rats

Wistar rats

30 male albino Wistar rats

30 Swiss albino mice

LNCaP human prostate cancer cells

Human cervix epitheloid carcinoma HeLa cells endogenous ERα (human hepatoma HepG2 cells) and ERβ (human colon adenocarcinoma DLD-1 cells) HT-29 colon cancer cell line

30–54 male and female guinea pigs

Study designs/sample size

10 days

8 days

6 weeks

2 groups: pretreatment (16 weeks) post-treatment (5 weeks) 10 weeks

16 weeks

24 h

72 h

–

8 weeks

Duration of study

20 mg/kg/bw, orally

50 mg/kg/bw, orally

20 mg/kg/bw, orally

50 mg/kg b. wt. orally

200 mg/kg/bw, orally

150 mg/kg/bw, orally

10–80 Amol/L

0.02 to 2.85 mmol

10 μM

9.2, 18.4 and 36.8 mg/kg/bw, orally

Dose

Ref

[115]

[114]

[81]

[36]

[24]

(continued on next page)

Up regulated peroxisome proliferator activated [94] receptor PPARγ Down regulated protein levels of AT1R, endothelin (ET)1, ET receptor type A (ETAR), extracellular signalregulated kinase (ERK)1/2, NFκB p65, oxidative/ endoplasmic reticulum (ER) stress, apoptosis, and inflammatory markers. Reduced serum creatinine, and kidney tissue levels of [95] MDA, NO, and interleukin-8 (IL-8); increased renal glutathione peroxidase activity; reduced gentamicininduced expression of kidney injury molecule-1 (KIM1), vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), and caspase-9 Decreased renal lipid peroxides. [96] Increased in renal antioxidant enzyme activity

[116] Ameliorated lipid peroxidation, ROS formation, aberrant crypt foci (ACF) and mucin depleted foci (MDF) and it also reduced mast cells infiltration, suppressed the immunostaining of NF-κB-p65, COX-2, i-NOS PCNA and Ki 67. It also attenuated the level of TNF-α and prevented the depletion of the mucous layer

Inhibited cell proliferation at doses greater than 0.71 mmol. Stimulated Base Excision Repair (BER) enzyme gene expression in LNCaP prostate cancer cells following an oxidative stress Decreased lipid peroxidation (LPO), proinflammatory cytokines; increased activities of tissue enzymatic and non-enzymatic antioxidants; decreased CYP1A1, NFκB, PCNA protein expression Modulated xenobiotic-metabolizing enzymes (XMEs); alleviated lipid peroxidation in both groups

Induced activation of p38/MAPK leading to the proapoptotic caspase-3 activation and to the poly(ADPribose) polymerase cleavage

[113] Reduced the concentrations of interleukin-8 (IL-8), leukotriene B4 (LTB4) and tumour necrosis factor-α (TNF-α) in BALF; decreased the myeloperoxidase (MPO) activity in both BALF and lung tissue; improved superoxidase dismutase (SOD) activity in lung tissue; increased the content of lipoxin A4 (LXA4) in BALF

Finding/result

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[98] 50 mg/kg/bw, orally 7 days

4 weeks

25 and 50 mg/kg/bw, orally

Decreased lipid peroxidation; increased in renal antioxidant Inhibited renal fibrosis by blocking Smad3 phosphorylation and transcription (NG) Decreased accumulation of collagen I and α-SMA+ myofibroblasts within the UUO kidney (NG + AA)

[97]

generation in the mitochondria is the initial trigger of diabetes mellitus [44]. Apart from the mitochondrial pathway, oxidative stress in diabetes originates from non-enzymatic and enzymatic pathway [44]. Enzymatic sources of augmented generation of reactive species in diabetes include nitric oxide synthase (NOS), nicotine adenine disphosphonucleotide (NADPH) oxidase and xanthine oxidase whereas in nonenzymatic pathway, glucose react with the proteins in the development of Amadori products cause more formation of AGE and more ROS along the process. The enhanced metabolism of glucose through polyol pathway also causes more superoxide formation [44]. It is interesting to note that different type of DM reacts differently towards oxidative stress. For an example complication from type 1 mainly mediated by ROS but complications arise from type 2 is mainly due to high nutrient influx which cause increase production of ROS and further loss of cell function [43]. Increase lipid peroxidation is one of the characteristic of chronic hyperglycaemia. It cause tissue damage by impairing the cell membrane fluidity and alters the activity of membrane-bound enzymes and receptors, resulting in membrane malfunction [31]. More substrate from chronic hyperglycaemia produced more free radicals. Increased lipid peroxidation and reduced antioxidant activity are observed in diabetic animal model [30]. Insulin resistance that associated with diabetes mellitus is related to the high caloric intake which exceeds the energy expenditure. This will cause increase in citric acid activity, production of mitochondrial NADH and ROS. To prevent the increment of the ROS, the cells need to washout the ROS overload or inhibit its overproduction [43]. The inhibition of ROS occurs by inhibiting the free fatty acid oxidation and prevents the accumulation of NADH in the mitochondria. The accumulation of free fatty acid intracellularly reduced GLUT4 translocation to plasma membrane, resulting in resistance to insulin-stimulated glucose uptake in muscle and adipose tissue. Multiple studies showed that antioxidants have been shown to improve insulin sensitivity [19, 30, 43, 44]. In diabetes, NG is believed to reduce the plasma glucose level [45]. Several animal studies had proven NG as anti-hyperglycaemic agent as well as it effect on the complications of diabetes [28, 29]. NG exerts its effect either by pancreatic or extra-pancreatic action. With regard to its extra pancreatic effect, NG reduces the glucose by impairing the glucose intake via Na+-GLUT co-transporter [46], insulin-induced glucose transporter (GLUT4) translocation [47] and inhibit intestinal alphaglucosidase [48]. NG stimulates insulin release from the pancreas to improve the glucose metabolism [49]. Apart from its anti-hyperglycaemic effect, NG is used as oxidative stress reliever in the treatment of diabetes mellitus. One of the consequences of chronic hyperglycaemia is the increase level of lipid peroxidation, malondialdehyde (MDA) secondary to oxidative stress. Studies showed that NG reduces the MDA level and controls the insult of lipid peroxidation in diabetes and serves as the anti-oxidant agent [15]. The effect of antioxidants in diabetes not only confined in the plasma, but there are significant reduction of enzymatic antioxidants in tissue such as liver, pancreas and kidney [13, 30]. An earlier study observed that NG improved the diabetic nephropathy in experiment type 1 diabetic rats via downregulation the TGF-β1 and IL-1 expression via modulation of oxidative stress and decreased cells apoptosis [50]. In animal study induced with alloxan showed that NG along with quercetin (flavonoid compound) have positive effect on the DNA damage caused by high level of oxidative stress in the diabetes mellitus. The study proved that high intake of flavonoid-rich compounds ameliorates the long-term complications of diabetes by reducing the oxidative stress and altering DNA damage in the liver and kidney of the experimental diabetic animal [51]. Another study agreed upon with the previous researchers and had observed that NG able to improve pathological alterations in organs of diabetic mice [52]. It significantly reduced the lipid peroxidation in the kidney and liver tissue and showed repair activity in the diabetic-induced kidney damaged. NG improves the lesion of cardiac hypertrophy by lowering oxidative stress and disarming c-Jun Nuclear Kinase-1 Protein in type I

Obstructive nephropathy-induced renal fibrosis mouse model In vivo 37.

NG and NG+ Asiatic acid (AA)

30 adult male albino rats of Wistar strain 40 C57BL6 male mice Drug-induced (cadmium) nephrotoxicity In vivo 36.

NG

Study model/subject No. Type of study

Table 1 (continued)

Single/ synergistic effect

Study designs/sample size

Duration of study

Dose

Finding/result

Ref

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diabetes which act as a key modulator in apoptosis [53]. NG also normalize glucose and lipid metabolism, and improved vascular dysfunction in type 2 diabetic rats by downregulating the oxidative stress and inflammation [54]. The study disclosed that NG inhibited NF-κB activation and ICAM-1 mRNA expression in Palmitic Acid-treated endothelial cells and enhanced nitric oxide production in the existence of insulin. In term of accelerating the process of cardiomyopathy in diabetes, hyperglycaemia promotes myocardial fibrotic lesions through upregulation or activation of PKC and p38 in response to the redox imbalance [42]. Naringenin also protects the nerve degeneration secondary to hyperglycaemia via the reduction of interleukins (IL) and oxidative stress markers [55]. This finding is probably useful in the treatment of diabetic neuropathy. Therefore, NG is believed to limit the progression of complications secondary to diabetes mellitus.

activates the antioxidant response element. Nrf2 is a transcription factor that translocate from the cytoplasm into the nucleus in an oxidative stress condition [65]. NG also protects dopaminergic neurons in the substantia nigra against neurodegeneration and oxidative damage in PD [66]. NG improves locomotor and increased glutathione with decrease MDA content in the brain tissue of PD rat model [67]. Studies on NG against neurodegenerative disease showed its anti-apoptotic property by inducing the glucose regulated protein 78 (GRP78) [68], the endoplasmic reticulum (ER) chaperone [69]; anti-inflammatory property via reducing the inflammatory cytokines and free radicals. All these findings pointed out that NG can be considered as potential neuroprotective agent via its antioxidant activity.

4.3. Naringenin and neurodegenerative disease

Exogenous pollutants like air pollutants, cigarette smoke, ambient high-altitude hypoxia are highly related to the development of the inflammatory pulmonary disease such as asthma and chronic obstructive pulmonary disease (COPD). On the other hand, ROS is generated endogenously during defence mechanisms against infectious pathogens such as bacteria, viruses, or fungi in the respiratory tract. ROS damages the tissues depending on the amount and duration of exposure. It acts as a trigger for enzymatically generated ROS released from respiratory, immune, and inflammatory cells [6]. The inflammation which occurred after the exposure to the oxidants will further recruit the other inflammatory cell and aggravate the oxidative stress in the lungs. These events lead to persistent inflammation, accompanied by chronic oxidative stress. The process then disturbs the protease-antiprotease balance, damages the tissue repair mechanisms, accelerated apoptosis and enhanced autophagy in lung tissues. Cigarette smoke which is one of the important environmental-derived ROS generates more than 1000 oxidants per puff and causes the increase in ROS. Increase in ROS induces lipid peroxidation and produced MDA as end products. MDA stimulate pulmonary inflammation and it increases in the peripheral circulation in patient with COPD [7]. The pathogenic process in COPD begins with inactivation of antiproteases thus enhancing bronchial inflammation by activating redox-sensitive transcription factors. Mucus glands become hyperplastic and produce more secretion. It then causes corticosteroid resistance, activates the neutrophils, macrophages, fibroblasts and abnormal airway T-cell population. Eventually, it causes small airway fibrosis and direct damage to respiratory cells. Increase in ROS causes gene polymorphisms and activation of transcription factor such as Nuclear factor kappa B (NF-κB) which contributes in the molecular pathogenesis of COPD [6]. In asthma, high oxidative stress triggered intracellular signalling cascades which induces inflammation via over expression of proinflammatory markers such as mitogen-activated protein kinase (MAPK), tumour necrosis factor (TNF)-alpha and NF-kB which in turn express the inflammatory cytokines like interleukins, chemokines, and adhesion molecules. These cytokines increase the oxidative stress, modulate the immune response and eventually cause cytotoxicity, enhance bronchial hyper-responsiveness, stimulate bronchospasm, and increase mucin secretion [70, 71]. The interleukins like IL-4 and IL-5 induce IgE production which are strongly associated with asthma progression [72]. NG exerts its effect as antioxidant in asthmatic animal model by reducing the mucus production. It also causes the reduction in interleukin which responsible to aggravate the mucus production and inflammation in the oxidative stress [73]. NG has synergistic effect with other flavonoids like hesperitin and significantly reduced infiltration of inflammatory cells in the airway and mucus plug formation. It also reduces the expression of TNF-α and transforming growth factor-β (TGF-β) in lung tissue that play a critical role in the pathogenesis of chronic asthma [74]. Treatment with NG significantly reduced the total serum IgE and T helper 2 (Th2) cytokines level in the bronchoalveolar lavage fluid (BALF) that delayed the progression of airway remodelling in allergen-induced murine asthma model [75]. Th2 is responsible in T-

4.4. Naringenin and pulmonary disease

Alzheimer and Parkinson diseases are the two commonest of among other chronic degenerative diseases like Huntington's disease and Amyotrophic Lateral Sclerosis. It is occurred sporadically without unknown causes. However, there is cumulative evidence postulated that oxidative stress leads to mitochondrial mutations/dysfunction which results in neuronal death and neural dysfunction [18]. Even though brain represents only 2% of the body weight, it consumes more than 20% of total oxygen consumption. Because of the high oxygen consumption and long-life duration of the neurons, it requires an effective anti-oxidative mechanism [5]. Alzheimer disease (AD) is a progressive neuronal loss disease characterised by aggregation of protein called beta-amyloid (βA) plaques or senile plaques and neurofibrillary tangles (NFTs) [56]. The imbalance of beta-amyloid peptide and tau protein which are responsible inducing oxidative stress and cause the progression of AD [56]. There are also evident of ROS-mediated injury where there is an increase in MDA and 4-hydroxynonenal in brain and cerebrospinal fluid of AD patients compared to controls [57, 58]. In Parkinson disease (PD), there is a progressive loss of dopaminergic neurons in the substantia nigra, and aggregation of the protein α-synuclein. The concentration of polyunsaturated free fatty acids in the substantia nigra is also reduced in the brain of PD patients, while the levels of lipid peroxidation markers are increased. It has been reported that there is an increase in the common deletions in mitochondrial DNA in the surviving dopaminergic neurons in PD substantia nigra, believed to be the result of oxidative stress [58]. Neuroinflammation plays an important role in the progression of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Sustained activation of nuclear transcription factor jB (NF-jB) is thought to play an important role in the pathogenesis of neurodegenerative disorders [59]. Recent scientific evidence suggests that oxidative stress, inflammation, metal accumulation, and mitochondrial dysfunctions accompany neurodegenerative diseases. Various physiological mechanisms are altered by these pathological changes which contribute to the aetiology of neurodegenerative diseases like PD and AD [60]. NG protects the neurodegeneration via its antioxidant and inflammatory mechanisms. In an earlier experimental study, a rat model was treated with NG following the beta-amyloid protein injection. The study showed the improvement in learning capabilities and memory by reducing the lipid peroxidation and apoptosis following NG treatment [61]. NG acts as an anticholinesterase and improves memory dysfunction in diabetes [62]. Patients with dementia in Parkinson disease (PD) and AD often have significant cholinergic defects due to loss of cholinergic neurotransmission [63]. NG has been used as the potential neuroprotective agent in the treatment of both diseases. Other studies suggested that pre-treatment with NG prevent neuronal injury and cognitive deficit induced by intracerebroventricular-streptozotocin [64]. It was postulated that treatment with NG in PD models increases nuclear factor E2-related factor 2 (Nrf2) protein level and further 118

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and apoptotic pathways resulting in greater inhibition of proliferation and cell viability compared to the single treatment. In the breast cancer, NG inhibits the tumour cells growth by inhibiting both the phosphoinositide 3-kinase (PI3K) and MAPK pathways and localizing oestrogen receptor (ER)α to the cytoplasm in the cell lines studied. NG is reported to induce apoptosis in other cancers such as colon, breast, and uterine cancer cell lines [88]. In the cell cycle, NG acts as an inhibitor to the cyclin E2 and induces apoptosis. At the same time, it prevents E2-induced extracellular regulated kinases (ERK1/2) and AKT activation then induces the activation of p38, the proapoptotic member of mitogen-activating protein kinase (MAPK) family [83]. As a result, NG acts as a chemopreventive agent in E2-dependent cancers [24, 89]. Treatment with NG in prostate cancer showed to impair the cell growth via its antioxidant property by inducing the base excision repair (BER) pathway [81]. However, the detailed mechanism on BER pathway was not well discussed. NG also maintains its proapoptotic effect in the presence of environmental food contaminant, bisphenol A (BPA). NG activates caspase-3 which inhibits cell growth in breast cancer cells in the present of BPA compound [90]. NG exerts its anti-carcinogenic effect in different form. However, the precise protective mechanism of NG on the cancer cells is still controversial. Study showed that new derivative of NG called oxime-NG is more effective anticancer agent [87]. Furthermore, NG enhances antitumor effect of doxorubicin by modulating drug efflux pathway and able to serve as a useful adjunct to improve the effectiveness of chemotherapeutic agents in treatment of human cancers [91]. From the above findings, it is believed that NG can be the novel chemotherapeutic candidate in the treatment of cancer.

cell immune and inflammatory pathways that initiate the immediate allergic response by releasing interleukins. Thr-2r induces the IgE production, stimulates and regulates the eosinophils production and promotes the growth of mucosal-type mast cells [72]. In condition of drug-induced pulmonary fibrosis, NG down-regulate TGF-h1 in the lungs which has been widely implicated in the development and progression of pulmonary fibrosis and promotes extracellular matrix gene transcription [76]. Hence, NG is believed to have beneficial effect on the oxidative stress related lung diseases. 4.5. Naringenin and cancer Over the years, the incidence of cancer among the aging population is reported to be increased. The carcinogenic agents are found in both domestic and industrial zones. Increased risk of cancer is well observed in older generation as they get prolong exposure to carcinogenic agents [77]. Under carcinogenic condition, mutated cells exhibit an accelerated metabolism, demand high ROS concentrations to maintain their high proliferation rate. ROS is used as a thermostat to monitor the cells damage. ROS regulation is highly important in cancer management as radiotherapeutics and chemotherapeutic drugs influence treatment outcome through ROS modulation. The mechanism in promoting tumour development and progression by ROS involves many pathways. It promotes cancer cells proliferation, apoptosis, angiogenesis and metastasis [20]. This leads to the DNA damage and impairs the cellular remodelling process thus enhances the progression of carcinogenesis [77, 78]. NG shows anti-proliferative effects in different cancer cell lines e.g., colon, breast, stomach, prostate, liver, cervix, pancreas, uterus and leukaemia cancer cell lines [79–82].Its anticancer effect manifested through selective cytotoxicity, anti-proliferative actions and by inducing apoptosis in dose-dependent [35]. NG inhibits tumour growth in sarcoma S-180-implanted mice [78]. NG also inhibits the mitogen activated protein kinas (MAPK) pathway to exert its anticancer effects. MAPKs are serine-threonine protein kinases that play the major role in signal transduction from the cell surface to the nucleus. Among others, MAPK pathway is responsible for the cell proliferation and differentiation, as well as inflammatory response. ROS is one of the stressor that activates MAPK signalling pathway [82]. Another study showed that NG exerts its anticarcinogenic effect by inhibiting the glucose uptake into the cells which in turn inhibit the cell growth [83]. Cancer cells require glucose as its energy sources to maintain the proliferation rate. NG establishes a stable and strong interaction at the ATP binding site of HER2-TK (HER2-tyrosine kinase) suggesting its role as HER2 inhibitors in HER2 positive breast cancer cell line [78]. NG inhibits other kinases such as CDK, MMP2 and Akt which are important in cancer signalling [84]. Metabolites of NG like 6-C-(E-phenylethenyl) Naringenin (6-CEPN), a small molecule found in Naringenin fortified fried beef, is capable to exert its anticancer effect by inhibiting the abnormal cell growth. It suppresses tumour cell proliferation through cell cycle arrest in G1 phase, induces necrotic cell death and autophagy in colon cancer cells. As cytoprotective autophagy, it blocks the autophagy by knock-down of the essential autophagy proteins. From the previous literatures, it is noted that the key mechanism of its anticancer effect might be by the inhibition of the Icmt/RAS signalling pathways [85]. NG metabolites, 6-CEPN, also inhibits COX-1 and impairs cell growth [86]. RAS oncoproteins is a molecule that responsible in 1/3 of all cancers due to its mutation that will lead to the excessive cell growth [85]. Apart from inhibiting kinases, there are other mechanism postulated that cause the cytotoxicity effect of NG. NG inhibits topoisomerase, and their pro-oxidant action which are responsible for the anti-proliferative activity [87]. NG also acts better in combination with other compounds. Studies of MCF-7 breast cancer cell lines showed the combination of NG and Tamoxifen is more effective [88]. The combination elicited its effects by targeting multiple proliferative

4.6. Naringenin and nephropathy Oxidative stress plays a role in a various renal disease such as glomerulonephritis and tubulointerstitial nephritis, chronic renal failure, proteinuria, uraemia. Sources for ROS in kidney diseases are activated macrophages, vascular cells and various glomerular cells, leucocytes and from renal interstitial cells [92]. Certain drugs such as cyclosporine [93], daunorubicin [94], gentamycin [95] and cisplatin [96] cause injury to the kidney. This drug induces nephrotoxicity, increases ROS production, induces inflammation and further aggravates the oxidative stress process. Heavy metals and transition metals also induce the nephropathy [1]. Study had shown that co-administration of NG with cyclosporine, a nephrotoxic agent, improved the kidney profile, renal lesion and increased the antioxidant parameters [93]. NG also protects the kidney from cisplatin-induced nephrotoxicity in the animal studies [96]. Cisplatin induces nephrotoxicity by generation of free radicals, lipid peroxidation in the membrane and subsequently develop oxidative stress. In nephrotoxic condition caused by gentamycin, NG ameliorates the effect by improving the biochemical parameters, antioxidant activity and abnormal morphology of the renal tissue. NG significantly reduced vascular endothelial growth factor, inducible nitric oxide synthase and caspase-9, and increased survivin expression in the kidney tissue [95]. NG slows down the development of nephrotoxicity following daunorubicin administration. Daunorubicin is used as chemotherapy for myeloblastic and acute lymphoblastic leukaemia. Coadministration with NG reduces renal fibrosis possibly via its action of antioxidants through inhibition of Angiotensin II type I receptor (AT1R) in animal studies [94]. Angiotensin II involved in the development of renal failure by causing the hypertrophy of renal cells, increasing the renal microvascular pressure, and inducing the apoptosis, ROS, podocyte autophagy and the inflammation. Thus, inhibition of AT1R decreases the level of ROS produced. Its nephroprotective effect and antioxidant properties are also recognised in a study in which NG reduces lipid peroxidation and increase renal antioxidant activity in a cadiuminduced nephrotoxicity [97]. In the case of renal fibrosis secondary to the metabolic disease, NG acts as smad3 inhibitor in TGF/smad signalling that prevent the fibrosis process. TGF/smad is molecule responsible for development of fibrosis in renal tissue following oxidative 119

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state. NG inhibits smad3 transcription and phosphorylation and eventually prevents fibrosis in the renal tissue [98]. The gathering evidences from the previous literature revealed that NG serves as the nephroprotective agent via its antioxidant activity.

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5. Conclusion The present review article highlighted a comprehensive information of the previous literature that have observed the potential antioxidant effect of Naringenin and its actions towards oxidative stress diseases. It also underlined the mechanistic pathway and challenges involved in therapeutic route of Naringenin. From this review, it was also observed that many studies have been conducted on Naringenin towards its anticancer effect via its antioxidant approach compared to the other diseases. It is revealed that several in vivo and in vitro studies bring positive effect on Naringenin in oxidative stress disorder. However, very few clinical studies involved Naringenin and its association with human subjects. Therefore, Naringenin could be the next beneficial compound for human studies in the hope that it can pave the way in the treatment of oxidative disorders. References [1] L.A. Pham-Huy, H. He, C. Pham-Huy, Free radicals, antioxidants in disease and health, Int. J. Biomed. Sci. 4 (2) (2008) 89–96. [2] B. Halliwell, Biochemistry of oxidative stress, Biochem. Soc. Trans. 35 (2007). [3] S. Toyokuni, K. Okamoto, J. Yodoi, H. Hiai, J.L. Rains, S.K. Jain, Oxidative stress, insulin signaling, and diabetes, Free Radic. Biol. Med. 50 (5) (2011) 567–575. [4] C. Fernández-mejía, Oxidative stress in diabetes mellitus and the role of vitamins with antioxidant actions, Am. J. Agric. Biol. Sci. (2013) 209–232. [5] S. Gandhi, A.Y. Abramov, Mechanism of oxidative stress in neurodegeneration, Oxid. Med. Cell. Longev. 2012 (2012) 428010, https://doi.org/10.1155/2012/ 428010 Epub 2012 May 16. [6] W. Domej, K. Oettl, W. Renner, Oxidative stress and free radicals in COPD-implications and relevance for treatment, Int. J. Chron. Obs. Pulmon. Dis. 9 (2014) 1207–1224. [7] S.F. van Eeden, D.D. Sin, Oxidative stress in chronic obstructive pulmonary disease: a lung and systemic process, Can. Respir. J. 20 (1) (2013) 27–29. [8] G. Block, M. Dietrich, E.P. Norkus, et al., Factors associated with oxidative stress in human populations, Am. J. Epidemiol. 156 (3) (2002) 274–285. [9] R.R. Hafidh, A.S. Abdulamir, F. Abu Bakar, F. Abas, F. Jahanshiri, Z. Sekawi, Antioxidant research in Asia in the period from 2000–2008, Am. J. Pharmacol. Toxicol. 4 (3) (2009) 48–66. [10] Z. Hussein, S.W. Taher, H.K. Gilcharan Singh, W. Chee Siew Swee, Diabetes care in Malaysia: problems, new models, and solutions, Ann. Glob. Health 81 (6) (2015) 851–862. [11] S. Farid, U. Akter, M. Fauzi, A. Rani, Dementia: prevalence and risk factors, Int. Rev. Social. Sci. Humanities. 2 (2) (2012) 176–184. [12] J. Lisa, M. Wilcox Nica, M.W.H. Borradaile, Antiatherogenic properties of naringenin, a citrus flavonoid, Cardiovasc. Drug Rev. 17 (2) (1999) 160–178. [13] A. Sharma, A.K. Patar, S. Bhan, Cytoprotective, antihyperglycemic and antioxidative effect of naringenin on liver and kidneys of Swiss diabetic mice, Int. J. Health. Sci. Res. 6 (2016) 118–131. [14] S.M. Jeon, H.K.H.J. Kim, H.K.H.J. Kim, et al., Hypocholesterolemic and antioxidative effects of naringenin and its two metabolites in high-cholesterol fed rats, Transl. Res. 149 (1) (2007) 15–21. [15] T. Annadurai, A.R. Muralidharan, T. Joseph, M.J. Hsu, P.A. Thomas, P. Geraldine, Antihyperglycemic and antioxidant effects of a flavanone, naringenin, in streptozotocin-nicotinamide-induced experimental diabetic rats, J. Physiol. Biochem. 68 (3) (2012) 307–318. [16] M. Valko, C.J. Rhodes, J. Moncol, M. Izakovic, M. Mazur, Free radicals, metals and antioxidants in oxidative stress-induced cancer, Chem. Biol. Interact. 160 (1) (2006) 1–40. [17] U. Forstermann, Nitric oxide and oxidative stress in vascular disease, Pflugers Arch. 459 (6) (2010) 923–939. [18] M.H. Yana, X. Wang, X. Zhu, Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease, Free Radic. Biol. Med. 62 (2013) 90–101. [19] A. Ceriello, E. Motz, Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited, Arterioscler. Thromb. Vasc. Biol. 24 (5) (2004) 816–823. [20] V. Sosa, T. Moliné, R. Somoza, R. Paciucci, H. Kondoh, M.E. Leonart, Oxidative stress and cancer: an overview, Ageing Res. Rev. 12 (1) (2013) 376–390. [21] J.B. Harborne, Comparative biochemistry of the flavonoids series II. 3Desoxyanthocyanins and their distribution in ferns and gesneriads, Phytochemistry 5 (1966) 589–600. [22] J. Kühnau, The flavonoids. A class of semi-essential food components: their role in human nutrition, World Rev. Nutr. Diet. 24 (1976) 117–191. [23] O.K. Chun, S.J. Chung, W.O. Song, Estimated dietary flavonoid intake and major

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