Accepted Manuscript

A recent review of citrus flavanone naringenin on metabolic diseases and its potential
sources for high yield-production

Naymul Karim, Zhenquan Jia, Xiaodong Zheng, Sunliang Cui, Wei Chen

PII: S0924-2244(18)30177-8
DOI: 10.1016/j.tifs.2018.06.012
Reference: TIFS 2253

To appear in: Trends in Food Science & Technology

Received Date: 15 March 2018

Revised Date: 24 June 2018
Accepted Date: 27 June 2018

Please cite this article as: Karim, N., Jia, Z., Zheng, X., Cui, S., Chen, W., A recent review of citrus
flavanone naringenin on metabolic diseases and its potential sources for high yield-production, Trends in
Food Science & Technology (2018), doi: 10.1016/j.tifs.2018.06.012.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.
 ACCEPTED MANUSCRIPT

1 A recent review of citrus flavanone naringenin on metabolic diseases and its

2 potential sources for high yield-production

PT
4 Naymul Karim1, Zhenquan Jia3, Xiaodong Zheng1, Sunliang Cui2*, Wei Chen1*

RI
1
6 Department of Food Science and Nutrition, National Engineering Laboratory of Intelligent Food

7 Technology and Equipment, Key Laboratory for Agro-Products Postharvest Handling of

SC
8 Ministry of Agriculture, Zhejiang Key Laboratory for Agro-Food Processing, Zhejiang

U
9 University, Hangzhou 310058, China. AN
2
10 Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang

11 University, Hangzhou 310058, China.

M

3
12 Department of Biology, The University of North Carolina at Greensboro, Greensboro, NC

13 27412, USA.
D

14
TE

15

16
EP

17
C

18 * Corresponding author:
AC

19 Prof. Wei Chen, Department of Food Science and Nutrition, Zhejiang University, 866 Yuhangtang

20 Road, Hangzhou 310058, China. E-mail: zjuchenwei@zju.edu.cn

21 Prof. Sunliang Cui, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058,

22 China. E-mail: slcui@zju.edu.cn

23

1
 ACCEPTED MANUSCRIPT

24 ABSTRACT

25 Background: Metabolic syndromes are the multi-metabolic abnormality characterized by

26 hyperlipidemia, obesity, hyperglycemia, diabetes, hypertension, cardiovascular disease, and

27 neuro-dysfunction. Naringenin, a naturally occurring flavanone compound, abundantly found in

PT
28 citrus fruit, has demonstrated diverse biological activities. In this context, the role of naringenin

RI
29 in the treatment of metabolic disease and alternative sources for high-yield production of

30 naringenin have recently drawn full scientific attention and become an important issue in

SC
31 research.

32 Scope and approach: This review focuses on recent findings of naringenin against metabolic

33
U
disorders including oxidative stress, hyperlipidemia, obesity, diabetes, inflammation, and organ
AN
34 toxicity. Also, this review highlights the potential sources of naringenin production.

Key findings and conclusions: Naringenin exerts its protective effect against metabolic diseases
M

35

36 through multiple mechanisms including its antioxidant activity by scavenging free radicals,
D

37 inducing antioxidant enzymes and targeting on phosphoinositide 3-kinase/protein Kinase

TE

38 B/nuclear factor (erythroid-derived 2)-like 2 (PI3K/Akt/Nrf2), nuclear factor (erythroid-derived

39 2)-like 2/antioxidant responsive element (NRf2/ARE), nuclear factor kappa-light-chain-enhancer

EP

40 of activated B cells (NF-kB), mitogen-activated protein kinase (MAPK), 3-hydroxy-3-methyl-

41 glutaryl-coenzyme A (HMG-CoA) reductase, peroxisome proliferator-activated receptor

C

42 (PPAR), and nitric oxide-cGMP-protein kinase G-induced KATP channel (NO-cGMP-PKG-

AC

43 KATP). Moreover, microbial production is recommended as a promising alternative method for

44 large-scale production of naringenin. In conclusion, naringenin is a promising compound for the

45 prevention and management of metabolic diseases. Further clinical studies and trials are needed

46 to prove its protective effects on metabolic syndrome in the human population.

2
 ACCEPTED MANUSCRIPT

47

48 Keywords: Naringenin; Metabolic diseases; Antioxidant activity; Potential sources

49

50 Introduction

PT
51 Metabolic syndromes (MetS) are characterized by a cluster of metabolic abnormalities,

RI
52 such as high blood pressure, hyperglycemia, central adiposity, dyslipidemia, and increase the risk

53 of cardiovascular disease, stroke, and type II diabetes (Kaur, 2014). Over the past decades, MetS

SC
54 has become a major public health issue as well as a clinical challenge for the world and its global

55 prevalence ranges from 10 to 84%, based on lifestyle, environmental, physiological,

56
U
biochemical, clinical and metabolic factors (Song, Yu, Chang, Wang, & An, 2017). According to
AN
57 National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII, governed by
M

58 the National Institutes of Health, United States) guidelines, the overall MetS prevalence in US

59 adults increased from 22 to 34% in the years of 2000 to 2005 (Mozumdar & Liguori, 2011;
D

60 Beltrán-Sánchez, Harhay, Harhay, & McElligott, 2013); while in Chinese adults, the prevalence
TE

61 was 21.3% in 2009 (Xi, He, Hu, & Zhou, 2013). A recent cohort study on MetS found that

62 childhood MetS and obesity from five years are correlated with approximately 2.4-fold higher
EP

63 risk for adulthood MetS, thereby childhood MetS and overweight have been suggested to be a

64 significant predictor for adulthood MetS (Koskinen, et al., 2017). MetS prevalence was shown in
C

65 upward trends not only in China but also in other Asia Pacific countries. Their study also
AC

66 revealed that females and/with urban residents have the highest MetS prevalence (Ranasinghe,

67 Mathangasinghe, Jayawardena, Hills, & Misra, 2017). For the prevention and cure from major

68 risk factors of MetS, people used various chemical and drug agents, such as Angiotensin-

69 Converting-Enzyme (ACE) inhibitors (Hypertension), Non-Sulfonylurea (Diabetes), and Statin-

3
 ACCEPTED MANUSCRIPT

70 lipid lowering agent (Hypercholesterolemia). Almost all the drugs produce some noticeable side-

71 effects, such as headache, dizziness, nausea, vomiting, rash, abdominal pain, liver disease,

72 kidney disease, muscle weakness, and lactate acidosis etc. (Palmer, 2004; Aksay, Yanturali,

73 Bayram, Hocaoğlu, & Kiyan, 2007; Camerino, et al., 2017).

PT
74 Several studies proved the inverse association between dietary polyphenols intake and

RI
75 MetS using body weight, blood pressure, blood glucose, insulin resistance, cholesterol, oxidative

76 stress markers, and inflammatory markers etc. (Wu, et al., 2014; Su, Feng, Zheng & Chen, 2016;

SC
77 Micek, et al., 2017; Chiva-Blanch & Badimon, 2017). Plant-derived polyphenols such as

78 phenolic acids, curcuminoids, stilbenes, lignans, flavonoids, flavonols, flavones, anthocyanins,

79
U
and others possess potential antioxidant, anti-inflammatory, anti-hypertensive, hepato-protective,
AN
80 cardio-protective, anti-diabetes, and anti-obesity activities (Chen, Feng et al. 2013; Chen, Shen,

Su, & Zheng, 2014; Bao, et al., 2016; Issa & Hussen Bule, 2015; Van Hul, et al., 2017; Ayoub,
M

81

82 et al., 2017). An Italian population-based research found that high polyphenols intake reduced
D

83 the mortality rate by about 30% in older adult subjects (Zamora-Ros, et al., 2013) suggesting
TE

84 beneficial effects of polyphenols on ameliorating aging and mortality. The polyphenol intakes of

85 Malaysian and Japanese people are 1218-4323 and 827-2157 mg/day respectively, while the
EP

86 Brazilian people’s intake polyphenol is only 451-461 mg/day (Niyogi, 2016). This country-wide

87 variation of polyphenol consumption may depend on plant source, food source, food habit
C

88 (vegetarian or non-vegetarian), food processing, and others. Among the dietary polyphenols in
AC

89 plants, the highest proportion is flavonoids for approximately 67% (Martin & Appel, 2010).

90 In this review, we provide the current developments on using naringenin against MetS

91 and its associated diseases. We first discuss the characteristics of naringenin including its

92 structural analysis and pharmacokinetics along with its metabolites. We then focus on recent

4
 ACCEPTED MANUSCRIPT

93 findings related to the protective effects of naringenin against MetS and its associated diseases.

94 Traditional extraction and purification methods of naringenin synthesis from natural sources are

95 limited by high cost, low yield and are also time-consuming. Naringenin production in

96 microorganisms is thus recommended as one of the alternative method to achieve high yield with

PT
97 low cost.

RI
98

99 Naringenin

SC
100 Naringenin (2,3-dihydro-5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) is a

101 bitter and colorless compound abundant in citrus fruit, such as lemon, orange, clementine, and

102
U
grapefruit (Esaki, et al., 1994; Erlund, 2004; Al-Dosari, Ahmed, Al-Rejaie, Alhomida, & Ola,
AN
103 2017). Grapefruit jams obtained by applying different types of heat treatment (e.g., osmotic

dehydration, microwave energy, and conventional heating) significantly decreased the fruit
M

104

105 phytochemicals (β-carotene and flavonoids) content. Based on their study, the total loss of β-
D

106 carotene and flavonoids in jams was approximately 53-86% and 33-47%, respectively. It
TE

107 indicates that fruit processing may also affect the naringenin content by degrading the heat-

108 sensitive compound and releasing the bound flavanone to processing environment (Igual, Garcia-
EP

109 Martinez, Camacho, & Martínez-Navarrete, 2013). Naringenin is readily soluble in the binary

110 solution of ethanol and water (Zhang, et al., 2013). Naringenin has the typical structure of a
C

111 flavanone that contains hydroxyl groups (at 5, 7 and 4′ positions). These hydroxyl groups can be
AC

112 substituted by different functional groups to produce structural analogs (Figure 1) (Erlund, 2004;

113 Krauze-Baranowska, et al., 2013). Naringenin has a single chiral center at the C-2 position,

114 which is responsible for its enantiomeric properties (Figure 1) (Yáñez, Andrews, & Davies,

115 2007).

5
 ACCEPTED MANUSCRIPT

116 Several structural analogs of naringenin have been identified from citrus fruit such as

117 naringenin-7-glucoside. Compared to naringenin-7-rhamnoglucoside, naringenin-7-glucoside has

118 exhibited well intestinal absorption (Felgines, et al., 2000; Bredsdorff, et al., 2010). 4′-O-methyl

119 naringenin and 3′-hydroxy-4′-O-methylnaringenin are two metabolites of naringenin known as

PT
120 isosakuranetin and hesperetin, respectively. Both metabolites were detected in lower amounts

RI
121 (approximately 2% of the total plasma flavanones) in rat plasma after consuming the synthetic

122 diet containing 0.5% naringin, a naringenin-7-O-neohesperidoside compound containing two

SC
123 rhamnose units at 7′ position of naringenin, for seven days (Silberberg, et al., 2006). Sakuranetin

124 (7-O-methylnaringenin) is obtained from rice and Polymnia fruticosa. This compound can also

125
U
be synthesized from naringenin by naringenin-7-O-methyltransferase (Shimizu, et al., 2012).
AN
126 Aromadedrin or dihydrokaempferol is a flavanonol, which is synthesized from naringenin by

transferring the plant-derived flavanone-3-hydroxylase enzyme into Escherichia coli (Tu, et al.,
M

127

128 2017; Han, et al., 2017). β-Glucosidases produced from Rhizopus azygosporus Yuan et Jong (a
D

129 food-grade fungal inoculator for soybean tempeh fermentation) can convert naringenin into
TE

130 eriodictyol sulfate and eriodictyol glucoside within 96 hours in culture medium (Gonzales, et al.,

131 2016).
EP

132 To date, a limited number of pharmacokinetics studies of naringenin has been published.

133 After the consumption of flavanone glycosides (e.g., naringin), these compounds reach the colon
C

134 and get hydrolyzed into aglycones (e.g., naringenin) by microflora. These flavanone aglycones
AC

135 are partially absorbed in the intestinal barrier (Felgines, et al., 2000; Manach, Morand, Gil-

136 Izquierdo, Bouteloup-Demange, & Remesy, 2003). Partial absorption of flavanone aglycones

137 and glucosides can occur through passive diffusion across the small intestine (Choudhury,

138 Chowrimootoo, Srai, Debnam, & Rice-Evans 1999; Felgines, et al., 2000; Serra, Mendes,

6
 ACCEPTED MANUSCRIPT

139 Bronze, & Simplício, 2008). Several studies explained that flavanones can be metabolized in the

140 intestinal and hepatic cells, and are then converted into glucuronic-/sulfo-conjugated derivatives

141 prior to excretion (Fuhr & Kummert, 1995; Ishii, Furuta, & Kasuya, 1997; Lee & Reidenberg,

142 1998; Bourian, et al., 1999; Wang, Chao, Hou, & Hsiu, 2006; Lin, Hou, Tsai, Wang, & Chao,

PT
143 2014). 10 min after naringenin administration (20 mg/kg) to rats, naringenin and its glucuronides

RI
144 were detected in concentrations four times higher in the plasma than in the brain tissue (Peng,

145 Cheng, Huang, Chen, & Tsai, 1998). In another extended study using microdialysis coupled with

SC
146 HPLC analysis, higher concentrations of naringenin were detected in liver and bile compared to

147 the brain in rats (Tsai, 2002). Plasma concentration and urinary excretion of naringenin

148
U
(estimated by HPLC analysis) can be considered as biomarkers for fruit and vegetable intake
AN
149 (Erlund, et al., 2002; Brevik, Rasmussen, Drevon, & Andersen, 2004; Mennen, et al., 2008).

There are a few reported clinical trials about naringenin on MetS. In a recent study on male
M

150

151 endurance athletes, the bioavailability of orange juice was assessed by the quantitative analysis
D

152 of urinary flavanone metabolites. The results showed that after consumption of 500 ml of orange
TE

153 juice, the total naringenin metabolites reached 76 µM in the urine sample of male endurance

154 athletes (Pereira-Caro, et al., 2017). In another trial, after consumption of 250 ml orange juice in
EP

155 Chinese volunteers (23-30 years), the total naringenin in urine reached approximately 22% of

156 intake content within 4-12 hours as measured by an ultra-fast liquid chromatography-
C

157 quadrupole-time-of-flight tandem mass spectrometer (Zeng, et al., 2017). Intake of 240 ml
AC

158 orange flavanone beverages (containing 15.41 mg naringenin) in healthy middle-aged men (30–

159 65 years) significantly (P<0·05) reduced the postprandial endothelial dysfunction as evaluated

160 by flow-mediated dilatation (FMD) of the brachial artery at 0-7 hours (Rendeiro, et al., 2016).

161 Six-months consumption of grapefruit juice (340 ml/day, containing 210 mg naringenin

7
 ACCEPTED MANUSCRIPT

162 glycosides) significantly improved the vascular endothelial function in postmenopausal women

163 (Habauzit, et al., 2015).

164 Several studies demonstrated that naringenin possessed different biological activities

165 (Figure 2). These include antidiabetic activity by reducing hepatic and pancreatic inflammation

PT
166 (Annadurai, Thomas, & Geraldine, 2013); an anti-metastatic effect by enhancing

RI
167 transglutaminase activity and polyamine depletion (Lentini, Forni, Provenzano, & Beninati,

168 2007); cytotoxic activity by inhibiting lung large cell carcinoma (COR-L23), amelanotic

SC
169 melanoma (C32), prostate adenocarcinoma cells (LNCaP) and human cancer cell proliferation

170 (Tundis, Loizzo, Menichini, Bonesi, & Colica, 2011); neuroprotective effects against colchicine-

171
U
induced cognitive dysfunction (Kumar, Dogra, & Prakash, 2010); renoprotective effects against
AN
172 cadmium (Cd)-induced renal dysfunction (Renugadevi & Prabu, 2009); anti-ulcerative effect by

inhibiting histidine decarboxylase (Parmar, 1983); anti-inflammatory activity by suppressing

M

173

174 Toll-like receptor 4/NF-κB signaling (Dou, et al., 2013); anti-photocarcinogenic activity by
D

175 stimulating melanogenesis (Chiang, Lin, Hsiao, Tsai, & Wen, 2011); and anti-bacterial activity
TE

176 by inhibiting Salmonella thypi in comparison with chloramphenicol (Agus, Achmadi, &

177 Mubarik, 2017).

EP

178

179 Antioxidant and free radical scavenging activity of naringenin

C

180 Oxidative stress is caused by an imbalance between oxidants and antioxidants.

AC

181 Overproduction of free radicals and peroxides can damage cell components such as lipid,

182 protein, and DNA, etc. (Chen, Zhuang, Li, Shen, & Zheng, 2013; Zhang, et al., 2017; Li, Bao, &

183 Chen, 2018). Naringenin can potentially protect from oxidative damage via scavenging free

184 radicals (Table 1).

8
 ACCEPTED MANUSCRIPT

185 As one of the xenobiotic metals, lead (Pb) can be detectable in all biological systems.

186 Exposure to lead (Pb) also causes cellular oxidative damage of various vital organs, such as liver,

187 kidney, heart, and others. Naringenin was reported to protect significantly (P<0.05) against lead

188 (Pb)-induced oxidative stress compared to control group as evaluated by biochemical, oxidative

PT
189 stress, and antioxidative markers in the serum, liver, and kidney (Wang, et al., 2012). Mershiba,

RI
190 Dassprakash, & Saraswathy (2013) reported that treatment of naringenin (20 or 50 mg/kg/day)

191 for 28 days significantly protects against arsenic (As)-induced oxidative damage in rat liver and

SC
192 kidney via exerting antioxidant effects and radical quenching action. Naringenin treatments also

193 significantly improved the serum and antioxidant enzymes biomarkers in a dose-dependent

194
U
manner; and restored the tissues pathological changes (Mershiba, Dassprakash, & Saraswathy,
AN
195 2013). Another study also revealed the protective effect of naringenin (5 or 10 mg/kg/day)

against arsenic (As)-induced oxidative damage in mice model (Roy, et al., 2014). On the other
M

196

197 hand, the ethanol extract of Citrus aurantium L. at doses of 100 and 300 mg/kg/day (naringenin
D

198 as the main component of citrus fruit) showed the anti-oxidative effects against chromium (VI)-
TE

199 induced lung dysfunction. The extract significantly alleviated the oxidative stress (MDA and

200 protein carbonyl levels) and antioxidant (GSH, sulfhydryl groups, NPSH, vitamin C, vitamin E,
EP

201 Na+ K+ ATPase, CAT, GPx, and SOD) profile of lung tissue, and reformed the tissue histology

202 (Soudani, et al., 2013). Naringenin alleviates the cadmium (Cd)-induced hepatic and renal
C

203 toxicity in mice (Das, Roy, Das, Bhattacharya, & Haldar, 2016). Tungsten (W) is a heavy metal
AC

204 and has been widely used in various household products and instruments. Human beings can also

205 easily be exposed to this metal by the environment. Treatment with naringenin was found to

206 attenuate the oxidative stress and antioxidant markers of blood, liver, and spleen in rats exposed

207 to sodium tungstate (3 months, 100 ppm in drinking water) (Sachdeva & Flora, 2014).

9
 ACCEPTED MANUSCRIPT

208 Naringenin reduced the sodium tungstate-induced oxidative stress through exerting metal

209 chelating activity.

210 Methanol: water (80:20) extract of Zea mays (naringenin-148 mg/kg) exhibited in vitro

211 antioxidant activity. Mice treated with such extracts also showed reduced malondialdehyde

PT
212 (MDA) levels and improved endogenous enzymes activities (Catalase (CAT), total peroxidase

RI
213 (TPX), superoxide dismutase (SOD)) in the liver, kidney, and brain (Ramos-Escudero, Muñoz,

214 Alvarado-Ortíz, Alvarado, & Yánez, 2012). It is recommended to isolate the naringenin

SC
215 compound from purple corn extracts to evaluate the specific antioxidant properties. Advanced

216 glycation endproducts (AGEs) produces the cellular oxidative damage and plays causative roles

217
U
in the development of different chronic diseases. Naringenin exerted anti-glycation activity by
AN
218 inhibiting total fluorescent AGEs and non-fluorescent carboxymethyl lysine (CML) formation

(Zhang, Hu, Chen, & Wang, 2014). As a result, naringenin can reduce the thermal protein
M

219

220 glycation, which could be a promising way to alleviate the oxidative stress.
D

221 UV light exposure to the skin causes aging or photocarcinogenesis by the formation of
TE

222 reactive oxygen species (ROS) known as photooxidative stress. Solanum lycopersicum (tomato)

223 contains lycopene, alpha-tocopherol, naringenin and other compounds. Co-incubation of

EP

224 lycopene (1 µM) and naringenin (10 µM) exhibited a protective effect against UV light-induced

225 human dermal fibroblasts cell (HDF) oxidative damage. It was evaluated by a decrease in ROS
C

226 formation and an increase in cell viability, carotenoid stability, and HO-1 expression (Fernandez-
AC

227 Garcia, 2014). It is indicated that naringenin could prevent oxidative degradation of carotenoids

228 via inducing HO-1 expression. Also, treatment with naringenin (through intraperitoneal injection

229 (i.p.), 20, 30, and 100 mg/kg) protected the hairless skin of mice from ultraviolet B (UVB)

230 irradiation-induced inflammation and oxidative damage. This treatment suppressed skin edema,

10
 ACCEPTED MANUSCRIPT

231 neutrophil recruitment, MMP-9 activity, pro-inflammatory cytokines, and oxidative stress

232 markers (O2•− production and gp91phox expression) compared to a non-irradiated control group

233 (Martinez, et al., 2015). The compound reduced the skin-damage by enhancing free radicals

234 scavenging activity, ameliorating endogenous antioxidants depletion, and inhibiting production

PT
235 of gp91phox-dependent O2•− and its derivatives.

RI
236 In a paraquat-induced human bronchial epithelial (BEAS-2B) cell model, naringenin (5-

237 100 µM) showed a cytoprotective effect against paraquat-induced intracellular ROS production.

SC
238 Naringenin upregulated the antioxidant-related gene expression (GPX2, GPX3, GPX5, and

239 GPX7), and activated expression of Nrf2 and its targeted gene (HO-1 and NQO1) (Podder, Song,

240
U
& Kim, 2014). High dose of retinoic acid play an essential role in inducing osteoporosis through
AN
241 oxidative stress. Naringenin (100 mg/kg) treatment significantly alleviated the oxidative damage

and bone mineral contents induced by retinoic acid (80 mg/kg) (Orsolic, et al., 2014). In Dalton's
M

242

243 Lymphoma Ascites (DLA) tumor-bearing mouse model, treatment with naringenin (50
D

244 mg/kg/day) significantly attenuated doxorubicin-induced toxicity and hypoxic condition. Here,
TE

245 the treatment improved the blood functional markers, antioxidant enzymes in tissues (kidney,

246 heart, lung, liver, spleen, and tumor), histopathological changes, and tumor-microenvironment as
EP

247 compared to a doxorubicin-treated group (Kathiresan, et al., 2016). During doxorubicin

248 chemotherapy, naringenin supplement prevented the doxorubicin-induced free radical generation
C

249 and maintained antioxidant levels in the tumor-microenvironment. As a newly derived

AC

250 compound from naringenin, naringenin-oxime exhibited the greater anticancer potential than

251 naringenin (Kocyigit, Koyuncu, Dikilitas, Bahadori, & Turkkan, 2016). Moreover, co-treatment

252 with cisplatin (7 mg/kg) and naringenin-oxime (20 and 40 mg/kg) significantly reduced the

253 cisplatin-induced adverse effects such as nephrotoxicity, neurotoxicity, hepatotoxicity, and

11
 ACCEPTED MANUSCRIPT

254 genotoxicity. The co-treatment modulated the altered oxidative stress, antioxidant, genotoxic

255 markers in serum and organs (Koyuncu, Kocyigit, Gonel, Arslan, & Durgun, 2017). Pretreatment

256 of naringenin-oxime may protect from cisplatin-induced oxidative damage of DNA. Gentamicin

257 is an aminoglycoside antibiotic against Gram-negative bacteria. However, it has potential side-

PT
258 effect, such as ototoxicity. Co-treatment with 120 mg/kg (i.p.) gentamicin and 50 mg/kg (p.o.)

RI
259 naringenin significantly minimized the gentamycin-induced ototoxicity compared to the group

260 given gentamycin alone. The ototoxicity was assessed by distortion product otoacoustic emission

SC
261 (DPOAE) and auditory brainstem response (ABR) measurements, oxidative and antioxidant

262 parameters, histology, and apoptosis (TUNEL assay) of cochleae (Kocak, et al., 2017).

263
U
Naringenin can suppress the gentamicin-induced ototoxicity via scavenging ROS, which are
AN
264 accumulated in the cochlea, and cause the cellular apoptosis and cell death. Benzo[a]pyrene is a

potent mutagen and carcinogen from incompletely burned organic matters. Naringenin (100
M

265

266 mg/kg BW) enhanced the antioxidant and anti-inflammatory effects against benzo[a]pyrene-
D

267 induced oxidative stress and pulmonary toxicity. The antioxidant and anti-inflammatory activity
TE

268 was determined by antioxidant enzyme activity markers, lung injury markers, lung histology, and

269 inflammatory markers (NF-kB and COX-2) (Ali, et al., 2017). Here, naringenin lowered the
EP

270 ROS-mediated oxidative damage and inflammation via exerting free radical scavenging activities

271 and modulating NF-kB signaling pathway. In H2O2-induced testicular dysfunction rats,
C

272 naringenin (50 mg/kg) significantly modulated the testis weight and oxidative stress/antioxidant
AC

273 markers (MDA, GSH, GST), when compared to a H2O2-treated control group. Naringenin

274 supplement alleviates H2O2-induced seminiferous tubules disorganization, germ cells detachment

275 from the seminiferous epithelium and basal membrane, sloughing of germ cells as well as

12
 ACCEPTED MANUSCRIPT

276 vacuolization in seminiferous tubules in the testis. (Sahin, Ozkaya, Cuce, Uckun, & Yologlu,

277 2017).

278

279 Anti-hyperlipidemic and anti-obesity effect of naringenin

PT
280 Hyperlipidemia is considered the prime symptom of obesity and associated metabolic

RI
281 diseases (Wu, Tang, et al., 2013; Wu, Yu, et al., 2013). Naringenin can effectively ameliorate the

282 dyslipidemic condition and obesity of different biological models (Table 1). 3-Hydroxy-3-

SC
283 methylglutaryl coenzyme A (HMG-CoA) reductase increases the intracellular cholesterol

284 synthesis, whereas the Acyl-coenzyme A: cholesterol O-acyltransferase (ACAT) enzyme

285
U
catalyzes the cholesterol esterification leading to atherosclerosis disease. Rats fed with
AN
286 experimental diet (containing 0.1% naringenin) for six months significantly lowered the plasma

and hepatic cholesterol content, fecal neutral sterols, and inhibited the HMG-CoA reductase and
M

287

288 ACAT activities when compared to a control group (received experimental diet without
D

289 naringenin supplement) (Lee, et al., 1999). Naringenin supplementation at 1% and 3% in a

TE

290 Western diet (high-fat diet) for 4 and 30 weeks respectively significantly alleviated dyslipidemia,

291 insulin resistance, glucose intolerance, and obesity compared to the western diet fed groups in
EP

292 LDL receptor knockout (Ldr(-/-)) mice and C57BL/6J mice (Mulvihill, et al., 2009). Moreover, a

293 supplement of 3% naringenin in the diet to (Ldr(-/-)) mice significantly prevented cholesterol-
C

294 induced dyslipidemia, insulin resistance, inflammation associated with the obesity and
AC

295 atherosclerosis disease as compared to control groups (Assini, et al., 2013). Naringenin can

296 increase hepatic fatty acid oxidation through PPARs, prevent SREBPs-mediated lipogenesis in

297 both liver and muscle, decrease hepatic cholesterol and cholesterol ester synthesis, reduce both

298 VLDL-derived and endogenously synthesized fatty acids. Cho, et al., (2011) reported that

13
 ACCEPTED MANUSCRIPT

299 experimental diet treatments (high-fat diet with naringenin - 0.003, 0.006, and 0.012%) to normal

300 rats led to maintenance of normal cholesterol levels. An experimental diet containing naringenin

301 reduced the plasma, liver, and adipose tissue lipid profile, and modulated the fatty acid

302 oxidation-related gene expression as compared to the control group (received only high fat diet)

PT
303 (Cho, Kim, Andrade, Burgess, & Kim, 2011). Naringenin may reduce the hyperlipidemia and

RI
304 obesity via activating the PPAR-α transcription factor and upregulating fatty acid oxidation-

305 related genes such as CPT-1 and UCP2. Zar Kalai, et al., (2013) demonstrated that naringenin

SC
306 (10 mg/kg) exerted anti-obesity effects against high fat diet-induced obese mice as evaluated by

307 enhancing the serum and hepatic lipid metabolism, lipolysis, and lipogenesis-related gene

308
U
expression, when compared to high-fat diet-fed group (Zar Kalai, et al., 2013). Furthermore, in
AN
309 3T3-L1 cell line, naringenin (6-50 g/mL) inhibited the adipogenesis on murine as evaluated by
M

310 reduced lipid accumulation and upregulated adipocyte protein expression (aP2, ADPN, PPAR ,

311 STAT5A) when compared to a control group (Richard, Amini-Vaughan, Ribnicky, & Stephens,
D

312 2013).
TE

313

314 Antidiabetic effect of naringenin

EP

315 Diabetes is a noncommunicable metabolic disorder which is characterized by sustained

316 hyperglycemia associated with either insulin resistance or absence of insulin production (Gowd,
C

317 Jia, & Chen, 2017). Naringenin can improve hyperglycemia by reducing insulin resistance and
AC

318 exerting antioxidant activity (Table 2). Acalypha wilkesiana (naringenin-11.12%) is a Southern

319 Nigerian plant and has been widely used to treat diabetes mellitus. The aqueous extract of

320 Acalypha wilkesiana leaves (doses-100, 200 and 300 mg/kg) treatments for 10 days to alloxan-

321 induced diabetic rats exhibited antidiabetic activity. The treatment significantly (P<0.05)

14
 ACCEPTED MANUSCRIPT

322 modulated the plasma markers (glycemia, lipid profile, hepato-specific profile, electrolyte

323 profile, atherogenic index, and hematology) and ocular oxidative stress markers as compared to

324 diabetic control group (Ikewuchi, Onyeike, Uwakwe, & Ikewuchi, 2011). Cola nitida seed

325 extract (3.6% naringenin content) inhibited the carbohydrate-digesting enzyme activities (α-

PT
326 amylase EC50 = 0.34 mg/mL and α-glucosidase EC50 = 0.32 mg/mL). The extract also inhibited

RI
327 the Fe2+-induced lipid peroxidation (MDA) in rat pancreas in a dose-dependent manner,

328 indicating its anti-diabetic activity (Oboh, Nwokocha, Akinyemi, & Ademiluyi, 2014).

SC
329 Hyperglycemia is associated with the production of ROS, which is related to cellular

330 genotoxicity in biological systems. In alloxan (75 mg/kg, i.v.)-induced diabetic mice, naringenin

331
U
(50 mg/kg, i.p., 7 days) reduced the peripheral lymphocytes DNA damage as evaluated by comet
AN
332 assay. Treatment with naringenin also significantly reduced the body weight, blood

hematological and immunological parameters as compared to diabetic mice (Orsolic, et al.,

M

333

334 2011). Naringenin showed a protective effect against diabetes, possibly by ameliorating
D

335 oxidative stress via improving antioxidant status. Kapoor, Rizvi, & Kakkar (2013) reported that
TE

336 pretreatment with naringenin (5 µg) protected against high-glucose (40 mM)-induced primary

337 hepatocyte apoptosis as confirmed by improved cell viability (MTT assay), ROS generation, and
EP

338 intracellular antioxidant profile (SOD, CAT, GPx). They also found that naringenin improved

339 the mitochondrial membrane potential (Cyt-c and AIF/Endo-G translocation), and suppressed the
C

340 caspase-9/3 activation, Bcl-2 family gene expression, intra-nucleosomal DNA damage and
AC

341 chromatin condensation (Kapoor, Rizvi, & Kakkar, 2013). These results suggested that

342 naringenin may alleviate the hepatic apoptosis of streptozotocin (STZ)-induced diabetes model.

343 In a Wistar rat model, co- and post-treatment with naringenin (50 mg/kg) was also found to

344 alleviate intracellular ROS generation, oxidative stress parameters, liver and kidney biomarkers.

15
 ACCEPTED MANUSCRIPT

345 The treatment further ameliorated the mitochondrial membrane dysfunction and expression of

346 genes encoding apoptotic proteins (Bax/Bcl-2, Caspase-3/9, AIF/Endo-G) (Kapoor, & Kakkar,

347 2014). As a result, naringenin can prevent high glucose-induced apoptosis via scavenging ROS

348 and modulate mitochondria-mediated apoptotic pathway.

PT
349 Furthermore, naringenin (5 and 10 mg/kg) protected from STZ-induced renal impairment.

RI
350 Treatment with naringenin for 10 weeks also significantly suppressed the biochemical and

351 oxidative stress parameters, renal degradation, TGF-β1/IL-1 upregulation, and kidney apoptosis

SC
352 (TUNEL assay) (Roy, Ahmed, Banerjee, & Saha, 2016). Here, naringenin lowered the

353 hyperglycemia-mediated oxidative damage, cytokines expression, apoptotic events, and thereby

354
U
alleviated the structural alterations of kidney such as glomerulosclerosis, glomerular basement
AN
355 membrane thickening, proximal and convoluted tubules changes, etc. Sirovina et al. (2016)

proved the hepato- and reno-protective effect of naringenin. Naringenin (50 mg/kg) ameliorated
M

356

357 the pathological changes of the liver such as unequal vacuolated, higher vacuolated around
D

358 central veins than Kiernan’s spaces, lymphocyte infiltrations. The treatment also alleviated the
TE

359 kidney architectural changes, e.g. renal corpuscles and tubules changes, narrow bowman’s

360 spaces, parietal layer's thickness, and tubule epithelium damage, etc. of diabetic mice compared
EP

361 to normal mice (Sirovina, Oršolić, Gregorović, & Končić, 2016).

362 STZ and nicotinamide (NA)-induced diabetic model exerts the East-Asian non-obese
C

363 type II diabetes (T2D) patients-like-phenotype (Nakamura, et al., 2006). In single-dose STZ (50
AC

364 mg/kg) and NA (110 mg/kg)-induced diabetic rats, naringenin (50 mg/kg) treatment ameliorated

365 hyperglycemia and oxidative stress (Annadurai, et al., 2012). Naringenin can reduce the diabetes

366 via possibly protecting pancreatic islets (preserve the remaining β-cell mass and reduce the

367 pancreatic islets vacuolization) from ROS-mediated oxidative stress. This compound also

16
 ACCEPTED MANUSCRIPT

368 stimulated the pancreatic β-cells to produce and secrete extra insulin to maintain glucose

369 homeostasis. Rahigude et al., (2012) reported the neuroprotective effect of naringenin against

370 high-fat diet (HFD)/high-fat emulsion (HFE) with STZ (single dose, 35 mg/kg)-induced T2D

371 rats. Naringenin (25, 50 mg/kg) treatments modulated the body weight, blood glucose, cognitive

PT
372 behavior dysfunction (reduce locomotor activity and inhibit cholinesterase activity), and

RI
373 biochemical changes (decrease MDA, NO, and GSH levels) of diabetic rats (Rahigude, Bhutada,

374 Kaulaskar, Aswar, & Otari, 2012). Naringenin can modulate the intracellular high-glucose-

SC
375 induced glucotoxicity in neuron via showing antioxidant activity, which can inhibit the

376 cholinesterase activity-induced memory dysfunction in diabetic condition. In addition, Al-Rejaie

377
U
et al. (2015) reported that naringenin (25 and 50 mg/kg, 2 weeks) ameliorated STZ (60 mg/kg)-
AN
378 induced diabetic neuropathy by lessening the serum glucose, pro-inflammatory cytokines (TNF-

α, IL-1β, IL-6), nitric oxide (NO) production, and oxidative stress markers (MDA). Naringenin
M

379

380 also improved the insulin levels, antioxidant enzyme activity (GSH, SOD, CAT, GPx, and GR),
D

381 insulin growth factor (IGF) and nerve growth factor (NGF) expression of sciatic nerve, and
TE

382 sciatic nerve histology (Al-Rejaie, et al., 2015). This study suggested that naringenin showed the

383 neuroprotective effect through increasing the activity of antioxidant enzymes of sciatic nerves.
EP

384 The reason is that the sciatic nerve cells might be more susceptible to damage by high-glucose-

385 induced oxidative stress. Retinal damage is one of the most common microvascular
C

386 complications of diabetes induced by oxidative stress. Naringenin (50 mg/kg) protected from
AC

387 STZ-induced retina damage by lowering hyperglycemia, oxidative stress markers, and apoptosis

388 markers (Bax/Bcl2, caspase-3). This compound also lowered the neuroprotective factors such as

389 brain-derived neurotrophic factor, tropomyosin-related kinase B and synaptophysin as compared

390 to a diabetic group (Al-Dosari, Ahmed, Al-Rejaie, Alhomida, & Ola, 2017). Naringenin may

17
 ACCEPTED MANUSCRIPT

391 limit neurodegeneration by providing neurotrophic support to protect from retinal damage in

392 diabetic retinopathy condition by reducing oxidative stress-induced apoptosis. Vascular

393 endothelial dysfunction is the common complication of T2D associated with NO production and

394 free fatty acids (FFA) generation. In HFD/STZ-induced diabetic rats and palmitic acid (PA)-

PT
395 induced human umbilical vein endothelial cells (HUVECs), naringenin treatments (50 or 100

RI
396 mg/kg for 6 weeks and 30 µM) minimized the vascular dysfunction. Naringenin significantly

397 alleviated the blood glucose and insulin levels, oxidative stress/antioxidant markers, intercellular

SC
398 adhesion molecule-1 (ICAM-1), thoracic aorta's pathology, insulin resistance (IR), and inhibited

399 the in-vitro NF-κB and ICAM-1 mRNA expression (Ren, et al., 2016). As a result, naringenin

400
U
can modulate vascular endothelial dysfunctions in diabetes condition at least in part by
AN
401 suppressing oxidative stress and inflammation. Naringenin itself acts as an enhancer for insulin-

secreting pancreatic endoderm (derived from human embryonic stem cells, hESCs) to reduce
M

402

403 gestational diabetes. Naringenin treatments to pancreatic endoderm transplanted gestational

D

404 diabetic mice increased the body weight, modulated the high blood glucose and low insulin
TE

405 levels, and improved the antioxidant status and reproductive outcome compared to the control

406 group (Xing, Yang, & Wu, 2016).

EP

407

408 Anti-inflammatory activity of naringenin

C

409 Inflammation is a complex biological response directly connected with oxidative stress,
AC

410 obesity, and diabetes; which can be ameliorated by naringenin (Table 2). In acetic acid- (4%)-

411 induced ulcerative colitis (a subtype of inflammatory bowel disease, IBD), different doses of

412 naringenin (25, 50, and 100 mg/kg) significantly lowered the colon weight/length, colon

413 histological changes such as colitis with superficial erosions, stromal edema, inflammatory cells

18
 ACCEPTED MANUSCRIPT

414 infiltration, and ulcerative mucosa. Naringenin also reduced the oxidative stress marker (MDA)

415 and inflammatory protein (TNF-α, IL-1β, IL-6, PGE2, and NO); increased the mucosal content,

416 antioxidant profile (T-GSH, NPSH, SOD, and CAT), total protein level, nucleic acid

417 concentration (DNA and RNA) as compared to an acetic acid treated group (Al-Rejaie, et al.,

PT
418 2013). There are several mechanisms which might explain anti-inflammatory activities of

RI
419 naringenin including NF-kB and activator protein-1 signals inhibition and increased

420 phosphorylation of ERK 5 and P38 MAPK. Naringenin cured the altered kidney and platelet

SC
421 injury of high cholesterol-fed rats showing an anti-inflammatory and anti-aggregate activity. Co-

422 treatments with cholesterol (10 gm/kg) and naringenin (50 mg/kg) for 3 months resolved the

423
U
hematological parameters, lipid profile, renal oxidative stress-related markers, and renal
AN
424 histology. The co-treatment also resolved the mRNA expression of kidney and platelets

membrane such as Ecto-nucleotide triphosphate diphosphohydrolases (NTPDases), ecto-5’-

M

425

426 nucleotidase (CD73), iNOS, TNF-α, IL-6, and NF-kB as compared to high-cholesterol-induced
D

427 group (Chtourou, et al., 2016). Lipopolysaccharide (LPS), an endotoxin from the outer
TE

428 membrane of the Gram-negative bacterial cell wall has been widely used for inducing

429 inflammation. Naringenin (50 and 100 mg/kg) exhibited anti-inflammatory activity against LPS-
EP

430 induced lung injury by decreasing wet/dry lung weight ratio and tissue biochemical profile

431 (MDA, NO, IL-6, and MPO). Naringenin also lowered the lung histological damage (tissue
C

432 damage, alveolar wall thickening, interstitial edema, and inflammatory cell infiltration) and lung
AC

433 immunohistochemical expression (NF-κB, iNOS, TNF-α, and caspase-3) (Fouad, Albuali, &

434 Jresat, 2016). Naringenin exerted protective effect against acute lung injury via upregulating heat

435 shock protein-70 (HSP70), which significantly reduced the inflammatory biomarkers (blocked

436 the NF-κB pathway) and impaired the apoptotic pathway (caspases). Another study reported that

19
 ACCEPTED MANUSCRIPT

437 naringenin lessened superoxide anion (KO2)-induced inflammatory pain in mice model via

438 modulating pain-like-behavior, mechanical hyperalgesia, and thermal hyperalgesia. The

439 treatment also reduced the MPO activity, oxidative stress-related markers, and cytokine

440 production (IL-33, IL-10, and TNF-α). In addition, naringenin activated the NO-cGMP-PKG-

PT
441 KATP channel and related Nrf2/HO-1 signaling pathway (Manchope, et al., 2016). Naringenin

RI
442 also reduced the LPS-induced inflammatory pain and leukocyte recruitment (Pinho-Ribeiro, et

443 al., 2016a). This study further showed that naringenin (50 mg/kg) treatment lowered the acute

SC
444 pain-behaviors and mechanical stimuli (such as carrageenan, capsaicin, and PGE2)-induced

445 inflammation (Pinho-Ribeiro, et al., 2016b). In UVB irradiation-induced skin damage,

446
U
naringenin containing tropical formulation treatment significantly lessened the skin edema,
AN
447 superoxide anion and lipid hydroperoxides production, and inflammatory cytokines (TNF-α, IL-

1β, IL-6, and IL-10). This formulation improved the mRNA expression of antioxidant markers
M

448

449 such as GPx-1, GR, Nrf2, and HO-1 as compared to an UVB-untreated group (Martinez, et al.,
D

450 2016). Naringenin treatments (25, 50 and 100 mg/kg) healed the thermal burn (10 sec immersion
TE

451 in 90°C water)-induced skin inflammation. Different doses of compound reversed the pro-

452 inflammatory cytokines (TNF- α, IL-1β, and IL-6), inflammatory markers (NO, PGE2, caspase-
EP

453 3, LT-B4, and NF-kB), oxidative stress parameters, and dermal histological changes (Al-

454 Roujayee, 2017). Naringenin may contribute to promote tissue regeneration via exhibiting
C

455 antioxidant activity (Nrf2/HO-1 pathway) and inhibiting inflammation (NF-kB pathway). In
AC

456 pemphigus vulgaris-treated human keratinocyte cell line (HaCaT), naringenin (50, 100 or 200

457 µM) reduced the cellular damage via modulating cellular apoptosis, antioxidant activity, and

458 cell-cell contacts disruption (cell fragments). Naringenin further modulated the ROS generation

459 and mitochondrial transmembrane potential, expression of keratinocyte adhesion molecules

20
 ACCEPTED MANUSCRIPT

460 (Dsg1, Dsg3, and E-cadherin) and NOD2- mediated NF-kB pathway (NOD2, RIPK2, and NF-kB

461 p-p65) (Liang, et al., 2017).

462

463 Hepato- and reno-protective effect of naringenin

PT
464 Naringenin showed hepato- and reno-protective effect via exhibiting antioxidant and free

RI
465 radical scavenging activity against oxidative stress induced by different toxicants such as

466 chemicals, drugs, heavy metals, etc. (Table 3). Oxytetracycline is an antibiotic that produces

SC
467 severe hepatic steatosis as an adverse effect. Oxytetracycline administration (i.p., 200 mg/kg for

468 15 days) significantly increased the hepato-specific biochemical profile such as aspartate

469
U
transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), lactate
AN
470 dehydrogenase (LDH), and bilirubin. Oxytetracycline drug also improved the oxidative stress

profile such as thiobarbituric acid reactive substances (TBARS) and lipid hydroperoxides,
M

471

472 reduced the antioxidant profile (Vit-C and -E, GSH, SOD, CAT, and GPx), and altered the
D

473 hepatic histology. However, oxytetracycline-induced hepatotoxicity was ameliorated by

TE

474 naringenin (50 mg/kg) treatment by reducing lipid peroxidation and enhancing cellular

475 antioxidant defense system (Pari & Gnanasoundari, 2006). Jayaraman, Veerappan, &
EP

476 Namasivayam (2009) also reported the hepatoprotective effect of naringenin against ethanol

477 (20%, 6 g/kg)-induced hepatotoxicity (Jayaraman, Veerappan, & Namasivayam, 2009). Carbon
C

478 tetrachloride (CCl4) is widely used to induce hepatic damage of animal model to evaluate the in
AC

479 vivo hepatoprotective effect of new compound or agent. In CCl4-induced acute hepatic failure,

480 naringenin (100 mg/kg) lessened the hepatic biochemical parameters, oxidative stress markers,

481 apoptosis markers (caspase-3, -8, and -9) (Yen, Wu, Lin, Cham, & Lin, 2009). Naringenin

482 treatments further lowered the pro-inflammatory protein (iNOS, COX-2, and TNF-α) via

21
 ACCEPTED MANUSCRIPT

483 upregulating the anti-oxidative defense protein (HO-1 and Nrf-2) (Esmaeili & Alilou, 2014).

484 Accumulation of heavy metals (such as cadmium (Cd), arsenic (As), lead (Pb), etc.) can damage

485 body organs via cellular oxidative damage by ROS. Naringenin (50 mg/kg) protected against

486 cadmium (Cd)-/arsenic (As)-/lead (Pb)- induced hepatotoxicity via exerting antioxidant

PT
487 scavenging activity (Renugadevi & Prabu, 2010; Jain, Yadav, Bozhkov, Padalko, & Flora, 2011;

RI
488 Ozkaya, Sahin, Dag, & Ozkaraca, 2016). In old-aged rats, naringenin treatment improved the

489 hepatic health, antioxidant status, and membrane phospholipid compositions (n-3 PUFA and n-

SC
490 6/n-3 PUFA ratio) in the liver tissue (Miler, et al., 2016). As a result, depletion of n-3 PUFA

491 content and enhancement of n-6/n-3 PUFA ratio is associated with age-related liver diseases,

492
U
which can be revised by naringenin. Hypercholesterolemia produces free fatty acids and induces
AN
493 lipotoxicity such as hepatic fibrosis or inflammation. Naringenin (50 mg/kg) significantly

lowered cholesterol-induced hepatic inflammation via decreasing plasma lipid profile, oxidative
M

494

495 stress profile, inflammatory markers (iNOS, Emr1, TNF-α, IL-1 β, IL-6, and NF-κB). This
D

496 compound further lessened the ECM dysregulation such as matrix metalloproteinases (MMP) -
TE

497 2/-9 expression and pro MMP-9/-2 activities, DNA fragmentation, and histological damages

498 (Chtourou, et al., 2015). Here, naringenin markedly lowered the lipid and protein oxidations,
EP

499 improved antioxidant status, and suppressed ECM degradation by modulating the levels of

500 necrotic inflammation. Simvastatin (SV) is used as a hypocholesterolemic drug that can cause
C

501 hepatic damage. Co-treatment with SV (20 and 40 mg/kg/day) and naringenin (50 mg/kg/day)
AC

502 exerted hepatoprotective effect via significantly modifying liver functions, oxidative stress

503 markers (MDA, GSH, SOD, GST, CAT), DNA fragmentation, and histopathological changes

504 compared to vehicle control and SV control (Motawi, Teleb, El-Boghdady, & Ibrahim, 2014).

505 Thus, concurrent treatment with SV and naringenin can manage the SV-induced hepatotoxicity,

22
 ACCEPTED MANUSCRIPT

506 which could be an effective treatment for hypercholesterolemia patients. Isoniazid and rifampicin

507 are the anti-tuberculosis drugs, and both can exert the hepatotoxic effect via generating ROS

508 causing the mitochondrial permeability and hepatocyte death. Naringenin (50 and 100 mg/kg)

509 protected from drugs (isoniazid and rifampicin)-induced oxidative stress and hepatic histological

PT
510 damage via possessing antioxidant and anti-apoptotic activities (inhibited the TUNEL positive

RI
511 cell, caspase-3, Bax/Bcl2 pathway) (Wang, Fan, Zhang, Nie, & Li, 2016).

512 Ethanolic extract of Algerian propolis- 100 mg/kg (contained 14.27% naringenin)

SC
513 significantly minimized the doxorubicin drug (10 mg/kg)-induced kidney toxicity. This extract

514 significantly restored the kidney profile (serum creatinine, γ-glutamyltranspeptidase enzyme

515
U
activity) as well as oxidative stress-related markers (MDA and GSH) (Boutabet, Kebsa, Alyane,
AN
516 & Lahouel, 2011). This extract reduced the kidney toxicity either by increasing the rate of GSH

or by scavenging free radicals. Hermenean et al., (2013) explained that naringenin protected (50
M

517

518 mg/kg) against CCl4-induced renal dysfunction. Naringenin treatments for seven days
D

519 significantly suppressed the renal oxidative stress-related markers (DA, SOD, CAT, GPx, and
TE

520 GSH). Naringenin treatment significantly reformed the pathohistological changes of kidney

521 tissue such as tubular renal epithelial vacuolization, glomerular atrophy, medulla area necrosis,
EP

522 collagen fibers around renal corpuscles and tubules, lipids proliferation in renal parenchyma,

523 TGF-β1 distribution in glomeruli and tubular areas, and T-cell immunoglobulin (TIM-1)
C

524 distribution in cortical area (Hermenean, et al., 2013). Nephroprotective effect of naringenin was
AC

525 also proved by Fouad et al., (2014). They suggested that naringenin protects against the

526 gentamycin-induced kidney toxicity as well as exhibiting antioxidant and anti-inflammatory

527 activities. The results revealed that naringenin treatments alleviated the renal parameter

528 (creatinine), oxidative stress-related markers (MDA and GPx), inflammatory markers (NO and

23
 ACCEPTED MANUSCRIPT

529 IL-8). They also observed that naringenin improved the renal architectural damages such as

530 tubular necrosis, tubular dilatation, vacuolization, epithelial lining desquamation, cast formation

531 in tubular lumen; and decreased the immunoreactivity (KIM-1, iNOS, VEGF, and caspase-9) of

532 the renal tubular cells (Fouad, Albuali, Zahran, & Gomaa, 2014). In daunorubicin drug-induced

PT
533 genotoxicity, naringenin ameliorated the kidney biochemical profile, renal histology, protein

RI
534 expression of AT1R and ERK1/2-NFκB p65 signaling pathway (p67phox, ET1, ETAR, p-

535 ERK1/2, p-NFκB p65, IFNγ, IL-6, TNFR1, and COX2). Naringenin also ameliorated the ER

SC
536 stress and apoptosis (GRP78, CHOP, cleaved caspase-7, and caspase-12 levels), and

537 inflammatory marker (PPARγ) (Karuppagounder, et al., 2015). Based on their research,

538
U
naringenin can improve the renal function of nephrotoxic rats via attenuating AT1R, ERK1/2-
AN
539 NFκB p65 signaling pathway.
M

540

541 Antihypertensive and cardioprotective effect of naringenin

D

542 Naringenin exhibits well-verified antihypertensive and cardioprotective effects (Table 3).
TE

543 In doxorubicin drug-induced cardiomyocytes (H9c2), naringenin-7-O-glucoside improved the

544 cell viability and cellular glutathione peroxidase (GSH-Px) activity. Naringenin-7-O-glucoside
EP

545 further lessened the cellular morphological injury, intracellular ROS generation and Ca2+

546 concentration, extracellular lactate dehydrogenase (LDH) content, and creatinine kinase (CK)
C

547 levels (Han, et al., 2012). According to their results, naringenin protected from cardiotoxicity by
AC

548 inhibiting cell death, increasing antioxidant activity, decreasing cellular calcium-overload, and

549 increasing mitochondrial function. Subburaman, Ganesan, & Ramachandran (2014) also

550 explained the protective effect against doxorubicin-induced cardiotoxicity in the rat model. They

551 found out that naringenin (50 mg/kg) treatments significantly modulated the body weight, heart

24
 ACCEPTED MANUSCRIPT

552 weight, cardiac enzymes markers (LDH activity and Troponin T (cTnT)), oxidative stress-related

553 parameters (MDA, SOD, CAT, and GPx). Naringenin treatment further revised the mRNA

554 expression of inflammatory markers (TGF-β1, TNF-α, IL-6, and IL-10), and cardiac tissue

555 architectural damage such as muscle fibers separation, inflammatory infiltration, myocardial

PT
556 tissue degeneration, and myofibrillar loss, etc. as compared to a doxorubicin-treated group

RI
557 (Subburaman, Ganesan, & Ramachandran, 2014). Also, naringenin reduced the H2O2-treated

558 H9c2 damage by reversing cell viability, oxidative stress-related parameters (glutathione, MDA,

SC
559 NO, catalase, GSH-Px, and GST). Naringenin modulated the gene transcription (Akt, NF-κB,

560 and caspase 3), and Nrf2/ARE signaling-mediated cellular defense system compared to a H2O2-

561
U
treated group (Ramprasath, et al., 2014). Authors found that naringenin showed a
AN
562 cardioprotective effect against oxidative stress-induced inflammatory stimuli by upregulating

Nrf2/ARE and Akt signaling pathway, and downregulating NF-kB and caspase 3-dependent
M

563

564 apoptosis pathway. Da Pozzo, et al. (2017) also proved that naringenin affected H2O2-induced
D

565 H9c2 cells senescence via modulating the ROS levels, DNA damage. Naringenin also modulated
TE

566 the mitochondrial potassium channels, mitochondrial oxidative metabolism activity, estradiol

567 level and estrogen-related pathways (ER and VDR) (Da Pozzo, et al., 2017). Besides in cardiac
EP

568 fibroblasts, naringenin improved the cardiac function via upregulating the Nrf2 and/or γ-

569 glutamylcysteine ligase (GCLc) expression-mediated antioxidant effect (Liu, An, & Gao, 2016).
C

570 Furthermore, naringenin inhibited the cholesterol-induced cardiotoxicity in rats, by altering the
AC

571 relative heart weights (%), cardiac lipid profile (TC, TG, FFA, and phospholipids), serum cardiac

572 markers (CK and LDH), and antioxidant status (CAT, GPx, SOD, GSH, NPSH, Vit C, and Vit

573 E). Naringenin treatment improved the heart mitochondrial enzymes markers (NADH

574 dehydrogenase, succinate-cytochrome c oxidoreductase, cytochrome c reductase, and ATP

25
 ACCEPTED MANUSCRIPT

575 synthase), reduced the cardiac cell death markers (TNF-α, Receptor interacting protein 3 (RIP3),

576 and DNA fragmentation), and cardiac tissue histological damage such as disorganized

577 myocardial fibers as compared to a disease control group (Chtourou, Slima, Makni, Gdoura, &

578 Fetoui, 2015). Naringenin reduced the cholesterol-induced cardiotoxicity, at least in part, by

PT
579 ameliorating RIP3-TNF-α mediated necroptosis pathway.

RI
580 In monocrotaline (60 mg/kg)-induced pulmonary hypertensive rats, co-treatments with L-

581 arginine (500 mg/kg) and naringenin (50 mg/kg) modified the body, heart, and lung weights,

SC
582 heart rate, blood pressure, electrocardiography, echocardiography. It also improved the oxidative

583 stress-related markers (MDA and GSH), inflammatory markers (MPO and TNF-α), nitric oxide

584
U
synthase (iNOS and eNOS), total nitrate/nitrite (NOx) level, apoptosis markers (TGF-β and
AN
585 caspase-3), and histological changes of the right ventricle and lung tissues (Ahmed, Obaid, Zaki,

& Agha, 2014). Therefore, this co-administration provided the additional benefits via improving
M

586

587 antioxidant activity, preserving NO beneficial effects, stimulating eNOS expression, and
D

588 inhibiting iNOS overexpression, and its associated inflammatory and apoptosis cascades.
TE

589 Methanolic extract of Schinus terebinthifolius (30 mg/kg) (containing naringenin) showed the

590 antihypertensive effect as evaluated by improved in vitro antioxidant activity, reduced blood
EP

591 pressure (systolic, median, and diastolic), and vasorelaxant effect (measured by rotarod test) (de

592 Lima Gloria, et al., 2017).

C

593
AC

594 Neuroprotective effect of naringenin

595 Metabolic syndromes are the major risk factors for neurodegeneration and congestive

596 dysfunction, which can be suppressed by naringenin (Table 3). Naringenin (25 and 50 mg/kg)

597 showed protective effect against chronic construction injury (CCI)-induced neuropathic pain in

26
 ACCEPTED MANUSCRIPT

598 the rat model by attenuating the pain-induced physical and behavioural changes (thermal

599 hyperalgesia, cold allodynia, mechanical hyperalgesia, and foot deformity) as well as oxidative

600 stress markers (MDA, GSH, and NO) (Kaulaskar, Bhutada, Rahigude, Jain, & Harle, 2012).

601 Authors suggested that naringenin lowered the neuropathic pain by inhibition of nitric oxide

PT
602 pathway and amelioration of oxidative stress. Intracerebroventricular-streptozotocin (ICV-STZ)

RI
603 (3 mg/kg; 5 µl per site) injection to rat significantly altered the normal behavior (spatial learning

604 and memory dysfunction), altered the non-enzymatic parameters in the hippocampus (4-HNE,

SC
605 MDA, TBARS, H2O2, PC, and GSH). ICV-STZ also reduced the enzymatic profiles in the

606 hippocampus (GPx, GR, GST, SOD, CAT, and Na+ K+- ATPase), decreased choline

607
U
acetyltransferase (ChAT) expression, and transformed the hippocampus histology such as
AN
608 shrunken neuron, dense/hyper chromatic nuclei, and clear space between neuron. All

abnormalities were reversed by naringenin pre-treatment (50 mg/kg) (Khan, et al., 2012).
M

609

610 Neuroprotective effect of naringenin against beta-amyloid (Aβ)-induced learning, and memory
D

611 dysfunction rats were further evaluated by improved behavioral change, hippocampus oxidative
TE

612 stress-related markers (MDA, nitrate level, and SOD) and apoptosis (DNA fragmentation)

613 (Ghofrani, et al., 2015). Their findings suggest that naringenin pretreatment attenuated the Aβ-
EP

614 induced Alzheimer’s disease via migrating lipid peroxidation and apoptosis, and its beneficial

615 effect was possibly mediated through the estrogenic pathway.

C

616 In an iron-induced rat model, naringenin lowered the cerebral cortex and hippocampus
AC

617 neurotoxicity by modifying behavioral changes such as anxiety-like behavior, locomotor activity,

618 and exploratory behavior. Naringenin further improved the oxidative stress-related markers,

619 antioxidant enzyme activities, mitochondrial enzyme markers, Na+/K+- ATPase, ChAT, and

620 ectonucleotidase activity, DNA fragmentation, and cerebral cortex histology (Chtourou, Fetoui,

27
 ACCEPTED MANUSCRIPT

621 & Gdoura, 2014; Chtourou, Slima, Gdoura, & Fetoui, 2015). Naringenin can modulate

622 cholinergic neurotransmission resting membrane potential of neurons via improving antioxidant

623 defense system and preserving the cellular integrity. These effects can improve the iron

624 overload-induced anxiogenic-like behavior, possibly by altering AChE and E-NTPDases

PT
625 activities. Exposure of tungsten (W) altered the normal neurological function by producing the

RI
626 neuro-oxidative damage. Naringenin (0.30 mM) treatment to tungsten (W) exposure rat,

627 significantly ameliorated the oxidative stress-related parameters (ROS, MDA, GSH, GSSG, and

SC
628 GPx), biogenic amines (dopamine, norepinephrine, and 5-hydroxytryptamine), brain AChE, and

629 MAO activity (Sachdeva, Pant, Kushwaha, Bhargava, & Flora, 2015). According to the authors,

630
U
naringenin exerted a neuroprotective effect by reducing sodium tungstate-induced oxidative
AN
631 stress, which leads to neurotransmitter levels alteration in different brain regions.

Hypoxia produced the behavioral changes (poking and rearing behavior) and neurological
M

632

633 damage by altering the hypoxic brain (neurons degeneration in the cortex, stratum radiatum, and
D

634 hippocampus region). Hypoxia also altered the protein and immunoexpression of cortex, stratum
TE

635 radiatum, and hippocampus (VEGF, HIF1α, Hsp70, Hsp90, CHIP panel, caspase-3, and

636 ubiquitination) compared to normoxia group, which is improved by naringenin (10 mg/kg)
EP

637 treatments (Sarkar, Angeline, Anand, Ambasta, & Kumar, 2012). Naringenin has the potential to

638 reverse the hypobaric hypoxia-mediated physiological impairments such as misfolded proteins
C

639 accumulation in the cellular environment, increased oxidative stress, and induction of apoptosis.
AC

640 All these biological disturbances effect leads to neuronal cell death and neurodegeneration.

641 Wang et al., (2017) unveiled that naringenin could protect against oxygen-glucose-deprivation

642 (OGD)-induced ischemic stroke. The results showed that naringenin treatment alleviated the

643 neuron cell proliferation, biochemical indices (ROS, MDA, and SOD), mitochondrial

28
 ACCEPTED MANUSCRIPT

644 dysfunction, cerebral oedema, and neurological defects. Naringenin also regulated the

645 localization of the Nrf2 protein and reduced the apoptosis markers (caspase -3/-9, Bax/Bcl2, and

646 DNA fragmentation) (Wang, et al., 2017). Naringenin can modulate the ischemic

647 cerebrovascular diseases by lowering apoptosis and oxidative stress through upregulating Nrf2

PT
648 signaling pathway. Combination of naringenin and lipoic acid (VNAL-100 mg/kg) also exerted

RI
649 the synergistic effect against OGD-induced hypoxia and reoxygenation of neuronal culture as

650 evaluated by LDH, SOD and intracellular antioxidant capacity (Saleh, Saleh, Connell, & Song,

SC
651 2017).

652 In mouse neuroblastoma cell line (Neuro 2A), naringenin (100 µM) reduced the carbaryl-

653
U
induced neurotoxicity via improving cell viability, ROS generation, mitochondrial membrane
AN
654 potential, expression of genes involved in apoptosis (Bax/Bcl2 and caspase-3) (Muthaiah,

Venkitasamy, Michael, Chandrasekar, & Venkatachalam, 2013). Based on their results from
M

655

656 MTT and FACS analysis, naringenin could improve the cell survival through maintaining the
D

657 mitochondrial membrane potential, upregulating anti-apoptotic gene Bcl-2, and downregulating
TE

658 pro-apoptotic genes (Bax and caspase-3). Naringenin (50 mg/kg) attenuated the ischemic stroke

659 in rat model via improving behavioral changes such as neurological deficits, motor function, grip
EP

660 performance, and somatosensory deficits. The treatment significantly modulated the altered

661 antioxidant profile, infarct size, and inflammatory parameters (MPO, NO, and cytokines). Also,
C

662 naringenin modified the protein and immuno expression of brain tissue (SOD, NF-kB, iNOS,
AC

663 COX-2, and Iba-1) (Raza, et al., 2013). According to their study, pretreatment of naringenin can

664 reduce cerebral ischemia/reperfusion injury by attributing anti-oxidant, free radical-scavenging,

665 and anti-inflammatory activities. These effects are more likely to be associated with the

666 downregulation of NF-kB signaling pathway. In 6-hydroxydopamine (6-OHDA)-induced

29
 ACCEPTED MANUSCRIPT

667 Parkinson's disease (PD) both in human neuroblastoma SH-SY5Y cells line and in mice model,

668 naringenin compound improved the cell viability, LDH release, ROS production, GSH level,

669 Nrf2/ARE pathway, and apoptotic signaling pathway (JNK/p38). Naringenin also improved the

670 immunoreactivity and protein expression of tyrosine hydroxylase (striatum and SNc section of

PT
671 the brain) (Lou, et al., 2014). Naringenin resolved the 6-OHDA-induced Parkinson's disease via

RI
672 activating Nrf2/ARE pathway and inhibiting apoptotic signaling pathway (JNK/p38). Naringenin

673 showed an anti-aging effect against D-galactose-induced behavioral dysfunction and

SC
674 neurological deficits via modifying body weight and organ index. Naringenin also modified the

675 behavioral changes (locomotion, spatial learning, and memory performance), brain

676
U
histopathological changes, neuronal loss and apoptosis (TUNEL and Nissl staining of
AN
677 hippocampus and cortex). This compound reduced the oxidative stress-related markers and

improved the endogenous antioxidant defense system by activating PI-3K/Akt/Nrf2 pathways

M

678

679 (Zhang, et al., 2017).

D

680
TE

681 Potential sources of naringenin

682 Naringenin production has become an attractive target because of its diverse biological
EP

683 functions in plants and beneficial effects on human. Normally, naringenin is obtained from citrus

684 fruit using the extraction and purification method. Generally, in plants, naringenin and its derived
C

685 flavonoid compounds are synthesized from the phenylpropanoid pathway. Except for some
AC

686 flavonoids, all the compounds can be biosynthesized from a common chalcone unit. Malonyl-

687 CoA and 4-coumaroyl-CoA serve as precursor molecules for naringenin biosynthesis. 4-

688 coumaroyl-CoA is produced by the enzymatic conversion of L-tyrosine or phenylalanine to 4-

689 coumaric acid via tyrosine ammonia lyase (TAL)/phenylalanine ammonia lyase (PAL) followed

30
 ACCEPTED MANUSCRIPT

690 by 4-coumarate: CoA ligase (4CL). The other precursor malonyl-CoA is originated from

691 carbohydrate metabolism pathway. In details, TAL and PAL convert tyrosine and phenylalanine

692 to the phenylpropanoids p-coumaric acid and cinnamic acid, respectively. Another additional

693 enzyme named cinnamate 4-hydroxylase (C4H) further converts the cinnamic acid to p-coumaric

PT
694 acid. After that, 4CL converts p-coumaric acid into 4-coumaroyl-CoA by using one molecule of

RI
695 ATP and one molecule of coenzyme-A (CoA). One molecule of activated 4-coumaroyl-CoA is

696 condensed with three malonyl-CoA by chalcone synthase (CHS) and formed the unstable yellow

SC
697 naringenin chalcone. The resulting unstable naringenin chalcone is converted into stable cyclic

698 naringenin by the chalcone isomerase (CHI) (Figure 3) (Lewinsohn, Britsch, Mazur, & Gressel,

699
U
1989; Martens & Mithöfer, 2005; Wu, Zhou, Du, Zhou, & Chen, 2014). Moreover, the addition
AN
700 of a sugar moiety with the naringenin aglycones sequentially converts the naringenin aglycones

into the naringenin glycosides (Figure 1) (Lewinsohn, Britsch, Mazur, & Gressel, 1989).
M

701

702 Distribution of naringenin in different parts of fruit depends on the concentrations of

D

703 biosynthesis enzymes. For example, in the Solanum lycopersicum peel, the level of CHS and
TE

704 flavanone 3-hydroxylase gene expression is higher than the CHI, indicating the accumulation of

705 high amount of naringenin chalcone (Iijima, Suda, Suzuki, Aoki, & Shibata, 2008). Isolation of
EP

706 naringenin from natural sources for biological research and commercial applications is

707 insufficient and has been engaged with various difficulties, such as low yield value, expensive
C

708 isolation method, time-consuming processing, seasonal availability, and region-specific

AC

709 availability, etc. For example, Luengo and team (2013) applied pulsed-electric field treatment for

710 extraction of polyphenol from orange peel. Even though their approaches improved the

711 production of naringenin from 1 to 3.1 mg/100 g of fresh orange peels (Luengo, Álvarez, &

712 Raso, 2013), the yield still shows limited output, when it is compared with microbial-assisted

31
 ACCEPTED MANUSCRIPT

713 production of naringenin (overall yield approximately 474.2 mg/L) (Xu, Ranganathan, Fowler,

714 Maranas, & Koffas, 2011). On the other hand, naringenin can be synthesized through a chemical

715 process. Acylation of 1,3,5-trimethoxybenzene with p-methoxycinnamic acid yielded 29%

716 naringenin (Wang, et al., 2015). The alternative method used in the same study exhibited the

PT
717 naringenin yield is of 45-60%. The process includes the conversion of 3,5-dimethoxyphenol into

RI
718 2-hydroxy-4,6-dimethoxyacetophenone followed by condensation with anisaldehyde to produce

719 2´-hydroxy-4,4´,6´-trimethoxychalcone. This chalcone is then cyclized and demethylated with

SC
720 aqueous HCl and pyridine hydrochloride to form naringenin (overall yield 45%). Also,

721 condensation of 2-hydroxy-4,6-dimethoxyacetophenone with anisaldehyde can produce 4´,5,7-

722
U
trimethoxyflavanone, which was then converted into naringenin with 60% yield (Wang, et al.,
AN
723 2015). However, these approaches are troubled with high-cost, complex reaction cascades, toxic

chemicals, and complex purification processes. As a result, alternative routes leading to

M

724

725 naringenin e.g., microbial biosynthesis are important to maximize the production rate, minimize
D

726 the cost and time, and to improve product safety as well as quality (Xie, Su, Sun, Zheng, &
TE

727 Chen, 2018). This is because microorganisms and plants share a similar primary metabolism

728 whereas the microorganisms naturally produce the precursors, such as phenylalanine, tyrosine,
EP

729 malonyl-CoA, etc. These precursor molecules are required to produce naringenin as well as other

730 polyphenols using microorganism platforms. For this reason, various strain and process
C

731 development for microbial naringenin production has become a recent interesting and attractive
AC

732 challenge in metabolic engineering (Milke, Aschenbrenner, Marienhagen, & Kallscheuer, 2018).

733

734 Overview and future directions

32
 ACCEPTED MANUSCRIPT

735 The monotherapy of conventional drug is a challenge to treat various diseases related to

736 metabolic syndrome. Clinical trial study of Vit-E treatment indicated an increase in the incidence

737 of cardiac failure (Investigators, 1999; Lonn, et al., 2005). In addition, Vit-C and -E treatments

738 exerted cardiovascular side-effects (Sesso, et al., 2008). These limitations of well-known

PT
739 antioxidant molecules create the new possibilities for investigating other bioactive compounds

RI
740 for the treatment of metabolic diseases. The studies discussed in this review showed that

741 naringenin exhibited the potential antioxidant, antihyperlipidemic, anti-obesity, anti-

SC
742 hyperglycemic, anti-diabetic, anti-inflammatory, anti-hypertensive, cardioprotective,

743 hepatoprotective, renoprotective, and neuroprotective activities (Figure 4). Dietary naringenin

744
U
and its derivatives exert effects by targeting various cellular signaling pathways including its
AN
745 antioxidant activity by scavenging free radicals, inducing antioxidant enzymes and targeting on

PI3K/Akt/Nrf2, NRf2/ARE, NF-kB, MAPK, HMG-CoA reductase, PPAR and NO-cGMP-PKG-

M

746

747 KATP channels. It is important to note that most of the studies have been conducted in either cell
D

748 type models or animal models (rat and mice). Therefore, further clinical study and trial are
TE

749 required to illustrate the protective effects of naringenin against metabolic syndromes in human.

750 However, such studies should consider the appropriate doses to be used to achieve its protective
EP

751 effects. People may increase the citrus fruit consumption as a source of dietary supplement since

752 naringenin is mostly obtained from the citrus fruit.

C

753 Due to low yield value, time-consuming extraction, and the high cost of purification steps,
AC

754 the alternative process of naringenin production is needed. Consecutive research on naringenin

755 biosynthesis in Saccharomyces cerevisiae, Streptomyces clavuligerus, and E. coli reported

756 production of pure naringenin with high yields from glucose (Milke, Aschenbrenner,

757 Marienhagen, & Kallscheuer, 2018). In conclusion, naringenin may be a suitable alternative

33
 ACCEPTED MANUSCRIPT

758 agent for the treatment of metabolic syndromes (Figure 4), and its production in microorganism

759 is one of the suitable alternative methods for achieving high-yield.

760

761 Abbreviations:

PT
762 ACAT, Acyl coenzyme A: cholesterol O-acyltransferase; ACE inhibitor, Angiotensin-

RI
763 converting-enzyme inhibitor; ADPN, Adiponutrin; STAT5A, Signal transducer and activator of

764 transcription 5A; AGEs, Advanced glycation endproducts; AIF, Apoptosis-inducing factor;

SC
765 ALP, Alkaline phosphatase; ALT, Alanine transaminase; aP2, Adipocyte protein 2; AST,

766 Aspartate transaminase; Bax, Bcl-2-associated X protein; Bcl-2, B-cell lymphoma 2; CAT,

767 Catalase; CCl4, Carbon tetrachloride;

U CFA, complete Freund’s adjuvant; CML,
AN
768 Carboxymethyllysine; COX-2, Cyclooxygenase-2; CPT-1, Carnitine palmitoyltransferase I;

Cyt-c, Cytochrome-c; DA, Dopamine; Dsg, Desmoglein; ENDO-G, Endonuclease-G; eNOS,

M

769

770 endothelial nitric oxide synthase; FFAs, Free fatty acids; FMD, Flow-mediated dilatation; GPx,
D

771 Glutathione peroxidase; GR, Glutathione reductase; GSH, Reduced glutathione; GST,
TE

772 Glutathione S-transferase; HFD, High fat diet; HFE, High fat emulsion; HMG-CoA, 3-hydroxy-

773 3-methylglutaryl coenzyme A; HO-1, Heme oxygenase-1; HPLC, High-performance liquid

EP

774 chromatography; HSP70,70 kilodalton heat shock proteins; ICAM-1, Intercellular adhesion

775 molecule-1; IFNγ, Interferon gamma; IGF, Insulin growth factor; IL-1, Interleukin-1; IL-1β,
C

776 Interleukin-1 beta; IL-6, Interleukin-6; iNOS, inducible nitric oxide synthase; IR, Insulin
AC

777 receptor; IBD, Inflammatory bowel disease; LDH, Lactate dehydrogenase; LDL, Low-density

778 lipoprotein; LT-B4, Leukotriene B4; MDA, Malondialdehyde; MetS, Metabolic syndrome;

779 MMP-9; Matrix metallopeptidase 9; MPO, Myeloperoxidase; NA, nicotinamide; Na+ K+

780 ATPase, Sodium-potassium adenosine triphosphatase; NCEP-ATPIII, National Cholesterol

34
 ACCEPTED MANUSCRIPT

781 Education Program-Adult Treatment Panel III; NF-κB, Nuclear factor-κB; NGF, Nerve growth

782 factor; NO, nitric oxide; NOD2, Nucleotide-binding oligomerization domain-containing protein

783 2; NPSH, Non-protein sulfhydryl; NQO1, NAD(P)H:quinone oxidoreductase-1; NRF2, Nuclear

784 factor erythroid 2 (NFE2) related factor 2; O2•−, Superoxide anion; PBQ, Phenyl-p-

PT
785 benzoquinone; PC, Protein carbonyl; PGE2, Prostaglandin E2; PPAR-α, Peroxisome

RI
786 proliferator-activated receptor alpha; RIPK2, Receptor-interacting serine/threonine-protein

787 kinase 2; ROS, Reactive oxygen species; SOD, Superoxide dismutase; STZ, Streptozotocin;

SC
788 T2D, type 2 diabetes; TGF-β1, Transforming growth factor beta 1; TIM-1, T-cell

789 immunoglobulin, TNF-α, Tumor necrosis factor alpha; TPX, Total peroxidase; TUNEL,

790
U
Terminal deoxynucleotidyl transferase dUTP nick end labeling; UCP2, Mitochondrial
AN
791 uncoupling protein 2.
M

792

793 Conflict of interest

D

794 The authors declare that there are no conflicts of interest.

TE

795

796 Acknowledgments
EP

797 This work was supported by Grants from Zhejiang Provincial Natural Science

798 Foundation of China (LR18C200002), National Natural Science Foundation of China

C

799 (U1703105), and the Fundamental Research Funds for the Central Universities (2017QNA6006).
AC

800

801 References

35
 ACCEPTED MANUSCRIPT

802 Agus, S., Achmadi, S. S., & Mubarik, N. R. (2017). Antibacterial activity of naringenin-rich

803 fraction of pigeon pea leaves toward Salmonella thypi. Asian Pacific Journal of

804 Tropical Biomedicine, 7, 725-728.

805 Ahmed, L. A., Obaid, A. A., Zaki, H. F., & Agha, A. M. (2014). Naringenin adds to the

PT
806 protective effect of L-arginine in monocrotaline-induced pulmonary hypertension in

RI
807 rats: favorable modulation of oxidative stress, inflammation and nitric oxide.

808 European Journal of Pharmaceutical Sciences, 62, 161-170.

SC
809 Aksay, E., Yanturali, S., BAYRAM, B., Hocaoğlu, N., & Kiyan, S. (2007). A rare side effect

810 of metformin: metformin-induced hepatotoxicity. Turkish Journal of Medical

811 Sciences, 37, 173-175.

U
AN
812 Al-Dosari, D. I., Ahmed, M. M., Al-Rejaie, S. S., Alhomida, A. S., & Ola, M. S. (2017).

Flavonoid Naringenin Attenuates Oxidative Stress, Apoptosis and Improves

M

813

814 Neurotrophic Effects in the Diabetic Rat Retina. Nutrients, 9, 1161.

D

815 Ali, R., Shahid, A., Ali, N., Hasan, S. K., Majed, F., & Sultana, S. (2017). Amelioration of
TE

816 Benzo[a]pyrene-induced oxidative stress and pulmonary toxicity by Naringenin in

817 Wistar rats: A plausible role of COX-2 and NF-kB. Human & Experimental
EP

818 Toxicology, 36, 349-364.

819 Al-Rejaie, S. S., Abuohashish, H. M., Al-Enazi, M. M., Al-Assaf, A. H., Parmar, M. Y., &
C

820 Ahmed, M. M. (2013). Protective effect of naringenin on acetic acid-induced

AC

821 ulcerative colitis in rats. World Journal of Gastroenterology, 19, 5633-5644.

822 Al-Rejaie, S. S., Aleisa, A. M., Abuohashish, H. M., Parmar, M. Y., Ola, M. S., Al-Hosaini,

823 A. A., et al. (2015). Naringenin neutralises oxidative stress and nerve growth factor

36
 ACCEPTED MANUSCRIPT

824 discrepancy in experimental diabetic neuropathy. Neurological research, 37, 924-

825 933.

826 Al-Roujayee, A. S. (2017). Naringenin improves the healing process of thermally-induced

827 skin damage in rats. Journal of International Medical Research, 45, 570-582.

PT
828 Annadurai, T., Muralidharan, A. R., Joseph, T., Hsu, M. J., Thomas, P. A., & Geraldine, P.

RI
829 (2012). Antihyperglycemic and antioxidant effects of a flavanone, naringenin, in

830 streptozotocin-nicotinamide-induced experimental diabetic rats. Journal of

SC
831 Physiology and Biochemistry, 68, 307-318.

832 Annadurai, T., Thomas, P. A., & Geraldine, P. (2013). Ameliorative effect of naringenin on

833
U
hyperglycemia-mediated inflammation in hepatic and pancreatic tissues of Wistar rats
AN
834 with streptozotocin- nicotinamide-induced experimental diabetes mellitus. Free

Radical Research, 47, 793-803.

M

835

836 Assini, J. M., Mulvihill, E. E., Sutherland, B. G., Telford, D. E., Sawyez, C. G., Felder, S. L.,
D

837 et al. (2013). Naringenin prevents cholesterol-induced systemic inflammation,

TE

838 metabolic dysregulation, and atherosclerosis in Ldlr(-)/(-) mice. Journal of Lipid

839 Research, 54, 711-724.

EP

840 Ayoub, H. M., McDonald, M. R., Sullivan, J. A., Tsao, R., Platt, M., Simpson, J., et al.

841 (2017). The Effect of Anthocyanin-Rich Purple Vegetable Diets on Metabolic

C

842 Syndrome in Obese Zucker Rats. Journal of Medicinal Food, 20, 1240-1249.
AC

843 Bao, T., Xu, Y., Gowd, V., Zhao, J., Xie, J., Liang, W., & Chen, W. (2016). Systematic study

844 on phytochemicals and antioxidant activity of some new and common mulberry

845 cultivars in China. Journal of Functional Foods, 25, 537-547.

37
 ACCEPTED MANUSCRIPT

846 Beltran-Sanchez, H., Harhay, M. O., Harhay, M. M., & McElligott, S. (2013). Prevalence

847 and trends of Metabolic Syndrome in the adult US population, 1999–2010. Journal of

848 the American College of Cardiology, 62, 697-703.

849 Bourian, M., Runkel, M., Krisp, A., Tegtmeier, M., Freudenstein, J., & Legrum, W. (1999).

PT
850 Naringenin and interindividual variability in interaction of coumarin with grapefruit

RI
851 juice. Experimental and Toxicologic Pathology, 51, 289-293.

852 Boutabet, K., Kebsa, W., Alyane, M., & Lahouel, M. (2011). Polyphenolic fraction of

SC
853 Algerian propolis protects rat kidney against acute oxidative stress induced by

854 doxorubicin. Indian Journal of Nephrology, 21, 101-106.

855
U
Bredsdorff, L., Nielsen, I. L., Rasmussen, S. E., Cornett, C., Barron, D., Bouisset, F., et al.
AN
856 (2010). Absorption, conjugation and excretion of the flavanones, naringenin and

hesperetin from alpha-rhamnosidase-treated orange juice in human subjects. British

M

857

858 Journal of Nutrition, 103, 1602-1609.

D

859 Brevik, A., Rasmussen, S. E., Drevon, C. A., & Andersen, L. F. (2004). Urinary excretion of
TE

860 flavonoids reflects even small changes in the dietary intake of fruits and vegetables.

861 Cancer Epidemiology and Prevention Biomarkers, 13, 843-849.

EP

862 Camerino, G. M., Musumeci, O., Conte, E., Musaraj, K., Fonzino, A., Barca, E., et al.

863 (2017). Risk of Myopathy in Patients in Therapy with Statins: Identification of

C

864 Biological Markers in a Pilot Study. Frontiers in Pharmacology, 8, 500.

AC

865 Chen, W., Feng, L., Shen, Y., Su, H., Li, Y., Zhuang, J., Zhang, L., & Zheng, X. (2013).

866 Myricitrin inhibits acrylamide-mediated cytotoxicity in human Caco-2 cells by

867 preventing oxidative stress. BioMed Research International, 2013, 724183.

38
 ACCEPTED MANUSCRIPT

868 Chen, W., Shen, Y., Su, H., & Zheng, X. (2014). Hispidin derived from Phellinus linteus

869 affords protection against acrylamide-induced oxidative stress in Caco-2 cells.

870 Chemico-Biological Interactions, 219, 83-89.

871 Chen, W., Zhuang, J., Li, Y., Shen, Y., & Zheng, X. (2013). Myricitrin protects against

PT
872 peroxynitrite-mediated DNA damage and cytotoxicity in astrocytes. Food Chemistry,

RI
873 141, 927-933.

874 Chiang, H. M., Lin, J. W., Hsiao, P. L., Tsai, S. Y., & Wen, K. C. (2011). Hydrolysates of

SC
875 citrus plants stimulate melanogenesis protecting against UV-induced dermal damage.

876 Phytotherapy Research, 25, 569-576.

877
U
Chiva-Blanch, G., & Badimon, L. (2017). Effects of Polyphenol Intake on Metabolic
AN
878 Syndrome: Current Evidences from Human Trials. Oxidative Medicine and Cellular

Longevity, 2017, 5812401.

M

879

880 Cho, K. W., Kim, Y. O., Andrade, J. E., Burgess, J. R., & Kim, Y. C. (2011). Dietary
D

881 naringenin increases hepatic peroxisome proliferators-activated receptor alpha protein

TE

882 expression and decreases plasma triglyceride and adiposity in rats. European Journal

883 of Nutrition, 50, 81-88.

EP

884 Choudhury, R., Chowrimootoo, G., Srai, K., Debnam, E., & Rice-Evans, C. A. (1999).

885 Interactions of the flavonoid naringenin in the gastrointestinal tract and the influence
C

886 of glycosylation. Biochemical and biophysical research communications, 265, 410-

AC

887 415.

888 Chtourou, Y., Fetoui, H., & Gdoura, R. (2014). Protective effects of naringenin on iron-

889 overload-induced cerebral cortex neurotoxicity correlated with oxidative stress.

890 Biological Trace Element Research, 158, 376-383.

39
 ACCEPTED MANUSCRIPT

891 Chtourou, Y., Fetoui, H., Jemai, R., Ben Slima, A., Makni, M., & Gdoura, R. (2015).

892 Naringenin reduces cholesterol-induced hepatic inflammation in rats by modulating

893 matrix metalloproteinases-2, 9 via inhibition of nuclear factor kappaB pathway.

894 European Journal of Pharmacology, 746, 96-105.

PT
895 Chtourou, Y., Kamoun, Z., Zarrouk, W., Kebieche, M., Kallel, C., Gdoura, R., et al. (2016).

RI
896 Naringenin ameliorates renal and platelet purinergic signalling alterations in high-

897 cholesterol fed rats through the suppression of ROS and NF-kB signaling pathways.

SC
898 Food & Function, 7, 183-193.

899 Chtourou, Y., Slima, A. B., Gdoura, R., & Fetoui, H. (2015). Naringenin Mitigates Iron-

900 Induced Anxiety-Like

U
Behavioral Impairment, Mitochondrial Dysfunctions,
AN
901 Ectonucleotidases and Acetylcholinesterase Alteration Activities in Rat

Hippocampus. Neurochemical Research, 40, 1563-1575.

M

902

903 Chtourou, Y., Slima, A. B., Makni, M., Gdoura, R., & Fetoui, H. (2015). Naringenin protects
D

904 cardiac hypercholesterolemia-induced oxidative stress and subsequent necroptosis in

TE

905 rats. Pharmacological Reports, 67, 1090-1097.

906 Da Pozzo, E., Costa, B., Cavallini, C., Testai, L., Martelli, A., Calderone, V., et al. (2017).
EP

907 The Citrus Flavanone Naringenin Protects Myocardial Cells against Age-Associated

908 Damage. Oxidative Medicine and Cellular Longevity, 2017, 9536148.

C

909 Das, A., Roy, A., Das, R., Bhattacharya, S., & Haldar, P. K. (2016). Naringenin Alleviates
AC

910 Cadmium-Induced Toxicity through the Abrogation of Oxidative Stress in Swiss

911 Albino Mice. Journal of Environmental Pathology, Toxicology and Oncology, 35,

912 161-169.

40
 ACCEPTED MANUSCRIPT

913 de Lima Gloria, L., Barreto de Souza Arantes, M., Menezes de Faria Pereira, S., de Souza

914 Vieira, G., Xavier Martins, C., Ribeiro de Carvalho Junior, A., et al. (2017). Phenolic

915 Compounds Present Schinus terebinthifolius Raddi Influence the Lowering of Blood

916 Pressure in Rats. Molecules, 22, 1792.

PT
917 Dou, W., Zhang, J., Sun, A., Zhang, E., Ding, L., Mukherjee, S., et al. (2013). Protective

RI
918 effect of naringenin against experimental colitis via suppression of Toll-like receptor

919 4/NF-kB signalling. British Journal of Nutrition, 110, 599-608.

SC
920 Erlund, I. (2004). Review of the flavonoids quercetin, hesperetin, and naringenin. Dietary

921 sources, bioactivities, bioavailability, and epidemiology. Nutrition Research, 24, 851-

922 874.
U
AN
923 Erlund, I., Silaste, M., Alfthan, G., Rantala, M., Kesdniemi, Y., & Aro, A. (2002). Plasma

concentrations of the flavonoids hesperetin, naringenin and quercetin in human

M

924

925 subjects following their habitual diets, and diets high or low in fruit and vegetables.
D

926 European Journal of Clinical Nutrition, 56, 891-899.

TE

927 Esaki, S., Nishiyama, K., Sugiyama, N., Nakajima, R., Takao, Y., & Kamiya, S. (1994).

928 Preparation and Taste of Certain Glycosides of Flavanones and of Dihydrochalcones.

EP

929 Bioscience, Biotechnology, and Biochemistry, 58, 1479-1485.

930 Esmaeili, M. A., & Alilou, M. (2014). Naringenin attenuates CCl4-induced hepatic
C

931 inflammation by the activation of an Nrf2-mediated pathway in rats. Clinical and

AC

932 Experimental Pharmacology and Physiology, 41, 416-422.

933 Felgines, C., Texier, O., Morand, C., Manach, C., Scalbert, A., Régerat, F., et al. (2000).

934 Bioavailability of the flavanone naringenin and its glycosides in rats. American

935 Journal of Physiology - Gastrointestinal and Liver Physiology, 279, 1148-54.

41
 ACCEPTED MANUSCRIPT

936 Fernandez-Garcia, E. (2014). Photoprotection of human dermal fibroblasts against ultraviolet

937 light by antioxidant combinations present in tomato. Food & Function, 5, 285-290.

938 Fouad, A. A., Albuali, W. H., & Jresat, I. (2016). Protective Effect of Naringenin against

939 Lipopolysaccharide-Induced Acute Lung Injury in Rats. Pharmacology, 97, 224-232.

PT
940 Fouad, A. A., Albuali, W. H., Zahran, A., & Gomaa, W. (2014). Protective effect of

RI
941 naringenin against gentamicin-induced nephrotoxicity in rats. Environmental

942 Toxicology and Pharmacology, 38, 420-429.

SC
943 Fuhr, U., & Kummert, A. L. (1995). The fate of naringin in humans: A key to grapefruit

944 juice‐drug interactions? Clinical Pharmacology & Therapeutics, 58, 365-373.

945
U
Ghofrani, S., Joghataei, M. T., Mohseni, S., Baluchnejadmojarad, T., Bagheri, M., Khamse,
AN
946 S., & Roghani, M. (2015). Naringenin improves learning and memory in an

Alzheimer's disease rat model: Insights into the underlying mechanisms. European
M

947

948 Journal of Pharmacology, 764, 195-201.

D

949 Gonzales, G. B., Smagghe, G., Wittevrongel, J., Huynh, N. T., Van Camp, J., & Raes, K.
TE

950 (2016). Metabolism of Quercetin and Naringenin by Food-Grade Fungal Inoculum,

951 Rhizopus azygosporus Yuan et Jong (ATCC 48108). Journal of Agricultural and
EP

952 Food Chemistry, 64, 9263-9267.

953 Gowd, V., Jia, Z., & Chen, W. (2017). Anthocyanins as promising molecules and dietary
C

954 bioactive components against diabetes – A review of recent advances. Trends in Food
AC

955 Science & Technology, 68, 1-13.

956 Habauzit, V., Verny, M. A., Milenkovic, D., Barber-Chamoux, N., Mazur, A., Dubray, C., et

957 al. (2015). Flavanones protect from arterial stiffness in postmenopausal women

42
 ACCEPTED MANUSCRIPT

958 consuming grapefruit juice for 6 mo: a randomized, controlled, crossover trial. The

959 American Journal of Clinical Nutrition, 102, 66-74.

960 Han, X. Z., Gao, S., Cheng, Y. N., Sun, Y. Z., Liu, W., Tang, L. L., et al. (2012). Protective

961 effect of naringenin-7-O-glucoside against oxidative stress induced by doxorubicin in

PT
962 H9c2 cardiomyocytes. BioScience Trends, 6, 19-25.

RI
963 Han, Y., Huang, K., Liu, Y., Jiao, T., Ma, G., Qian, Y., et al. (2017). Functional Analysis of

964 Two Flavanone-3-Hydroxylase Genes from Camellia sinensis: A Critical Role in

SC
965 Flavonoid Accumulation. Genes, 8, 300.

966 Hermenean, A., Ardelean, A., Stan, M., Herman, H., Mihali, C. V., Costache, M., et al.

967
U
(2013). Protective effects of naringenin on carbon tetrachloride-induced acute
AN
968 nephrotoxicity in mouse kidney. Chemico-Biological Interactions, 205, 138-147.

Igual, M., Garcia-Martinez, E., Camacho, M., & Martínez-Navarrete, N. (2013). Jam
M

969

970 processing and storage effects on β-carotene and flavonoids content in grapefruit.
D

971 Journal of Functional Foods, 5, 736-744.

TE

972 Iijima, Y., Suda, K., Suzuki, T., Aoki, K., & Shibata, D. (2008). Metabolite profiling of

973 chalcones and flavanones in tomato fruit. Journal of the Japanese Society for
EP

974 Horticultural Science, 77, 94-102.

975 Ikewuchi, J. C., Onyeike, E. N., Uwakwe, A. A., & Ikewuchi, C. C. (2011). Effect of
C

976 aqueous extract of the leaves of Acalypha wilkesiana 'Godseffiana' Muell Arg
AC

977 (Euphorbiaceae) on the hematology, plasma biochemistry and ocular indices of

978 oxidative stress in alloxan induced diabetic rats. Journal of Ethnopharmacology, 137,

979 1415-1424.

43
 ACCEPTED MANUSCRIPT

980 Investigators, G.-P. (1999). Dietary supplementation with n-3 polyunsaturated fatty acids and

981 vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. The

982 Lancet, 354, 447-455.

983 Ishii, K., Furuta, T., & Kasuya, Y. (1997). Determination of naringin and naringenin in

PT
984 human urine by high-performance liquid chromatography utilizing solid-phase

RI
985 extraction. Journal of Chromatography B: Biomedical Sciences and Applications,

986 704, 299-305.

SC
987 Issa, I. A., & Hussen Bule, M. (2015). Hypoglycemic Effect of Aqueous and Methanolic

988 Extract of Artemisia afra on Alloxan Induced Diabetic Swiss Albino Mice. Evidence-

989
U
Based Complementary and Alternative Medicine, 2015, 752486.
AN
990 Jain, A., Yadav, A., Bozhkov, A. I., Padalko, V. I., & Flora, S. J. (2011). Therapeutic

efficacy of silymarin and naringenin in reducing arsenic-induced hepatic damage in

M

991

992 young rats. Ecotoxicology and Environmental Safety, 74, 607-614.

D

993 Jayaraman, J., Veerappan, M., & Namasivayam, N. (2009). Potential beneficial effect of
TE

994 naringenin on lipid peroxidation and antioxidant status in rats with ethanol-induced

995 hepatotoxicity. Journal of Pharmacy and Pharmacology, 61, 1383-1390.

EP

996 Kapoor, R., & Kakkar, P. (2014). Naringenin accords hepatoprotection from streptozotocin

997 induced diabetes in vivo by modulating mitochondrial dysfunction and apoptotic

C

998 signaling cascade. Toxicology Reports, 1, 569-581.

AC

999 Kapoor, R., Rizvi, F., & Kakkar, P. (2013). Naringenin prevents high glucose-induced

1000 mitochondria-mediated apoptosis involving AIF, Endo-G and caspases. Apoptosis,

1001 18, 9-27.

44
 ACCEPTED MANUSCRIPT

1002 Karuppagounder, V., Arumugam, S., Thandavarayan, R. A., Pitchaimani, V., Sreedhar, R.,

1003 Afrin, R., et al. (2015). Naringenin ameliorates daunorubicin induced nephrotoxicity

1004 by mitigating AT1R, ERK1/2-NFkappaB p65 mediated inflammation. International

1005 Immunopharmacology, 28, 154-159.

PT
1006 Kathiresan, V., Subburaman, S., Krishna, A. V., Natarajan, M., Rathinasamy, G., Ganesan,

RI
1007 K., et al. (2016). Naringenin Ameliorates Doxorubicin Toxicity and Hypoxic

1008 Condition in Dalton's Lymphoma Ascites Tumor Mouse Model: Evidence from

SC
1009 Electron Paramagnetic Resonance Imaging. Journal of Environmental Pathology,

1010 Toxicology and Oncology, 35, 249-262.

1011
U
Kaulaskar, S., Bhutada, P., Rahigude, A., Jain, D., & Harle, U. (2012). Effects of naringenin
AN
1012 on allodynia and hyperalgesia in rats with chronic constriction injury-induced

neuropathic pain. Journal of Chinese Integrative Medicine, 10, 1482-1489.

M

1013

1014 Kaur, J. (2014). A Comprehensive Review on Metabolic Syndrome. Cardiology Research

D

1015 and Practice, 2014, 943162.

TE

1016 Khan, M. B., Khan, M. M., Khan, A., Ahmed, M. E., Ishrat, T., Tabassum, R., et al. (2012).

1017 Naringenin ameliorates Alzheimer's disease (AD)-type neurodegeneration with

EP

1018 cognitive impairment (AD-TNDCI) caused by the intracerebroventricular-

1019 streptozotocin in rat model. Neurochemistry International, 61, 1081-1093.

C

1020 Kocak, I., Sarac, S., Aydogan, E., Senturk, E., Akakin, D., Koroglu, K., et al. (2017).
AC

1021 Evaluation of the possible protective role of naringenin on gentamicin-induced

1022 ototoxicity: A preliminary study. International Journal of Pediatric

1023 Otorhinolaryngology, 100, 247-253.

45
 ACCEPTED MANUSCRIPT

1024 Kocyigit, A., Koyuncu, I., Dikilitas, M., Bahadori, F., & Turkkan, B. (2016). Cytotoxic,

1025 genotoxic and apoptotic effects of naringenin-oxime relative to naringenin on normal

1026 and cancer cell lines. Asian Pacific Journal of Tropical Biomedicine, 6, 872-880.

1027 Koskinen, J., Magnussen, C. G., Sinaiko, A., Woo, J., Urbina, E., Jacobs, D. R., et al. (2017).

PT
1028 Childhood Age and Associations Between Childhood Metabolic Syndrome and Adult

RI
1029 Risk for Metabolic Syndrome, Type 2 Diabetes Mellitus and Carotid Intima Media

1030 Thickness: The International Childhood Cardiovascular Cohort Consortium. Journal

SC
1031 of the American Heart Association, 6, 5632.

1032 Koyuncu, I., Kocyigit, A., Gonel, A., Arslan, E., & Durgun, M. (2017). The Protective Effect

1033
U
of Naringenin-Oxime on Cisplatin-Induced Toxicity in Rats. Biochemistry Research
AN
1034 International, 2017, 9478958.

Krauze-Baranowska, M., Poblocka-Olech, L., Glod, D., Wiwart, M., Zielinski, J., & Migas,
M

1035

1036 P. (2013). HPLC of flavanones and chalcones in different species and clones of Salix.
D

1037 Acta Poloniae Pharmaceutica, 70, 27-34.

TE

1038 Kumar, A., Dogra, S., & Prakash, A. (2010). Protective effect of naringin, a citrus flavonoid,

1039 against colchicine-induced cognitive dysfunction and oxidative damage in rats.

EP

1040 Journal of Medicinal Food, 13, 976-984.

1041 Lee, S. H., Park, Y. B., Bae, K. H., Bok, S. H., Kwon, Y. K., Lee, E. S., et al. (1999).
C

1042 Cholesterol-lowering activity of naringenin via inhibition of 3-hydroxy-3-

AC

1043 methylglutaryl coenzyme A reductase and acyl coenzyme A:cholesterol

1044 acyltransferase in rats. Annals of Nutrition & Metabolism, 43, 173-180.

46
 ACCEPTED MANUSCRIPT

1045 Lee, Y. S., & Reidenberg, M. M. (1998). A Method for Measuring Naringenin in Biological

1046 Fluids and Its Disposition from Grapefruit Juice by Man. Pharmacology, 56, 314-

1047 317.

1048 Lentini, A., Forni, C., Provenzano, B., & Beninati, S. (2007). Enhancement of

PT
1049 transglutaminase activity and polyamine depletion in B16-F10 melanoma cells by

RI
1050 flavonoids naringenin and hesperitin correlate to reduction of the in vivo metastatic

1051 potential. Amino Acids, 32, 95-100.

SC
1052 Lewinsohn, E., Britsch, L., Mazur, Y., & Gressel, J. (1989). Flavanone Glycoside

1053 Biosynthesis in Citrus Chalcone Synthase, UDP-Glucose: Flavanone-7-O-Glucosyl-

1054
U
Transferase and-Rhamnosyl-Transferase Activities in Cell-Free Extracts. Plant
AN
1055 physiology, 91, 1323-1328.

Li, Y., Bao, T., & Chen, W. (2018). Comparison of the protective effect of black and white
M

1056

1057 mulberry against ethyl carbamate-induced cytotoxicity and oxidative damage. Food
D

1058 Chemistry, 243, 65-73.

TE

1059 Liang, J., Halipu, Y., Hu, F., Yakeya, B., Chen, W., Zhang, H., et al. (2017). Naringenin

1060 protects keratinocytes from oxidative stress injury via inhibition of the NOD2-
EP

1061 mediated NF-κB pathway in pemphigus vulgaris. Biomedicine & Pharmacotherapy,

1062 92, 796-801.

C

1063 Lin, S.-P., Hou, Y.-C., Tsai, S.-Y., Wang, M.-J., & Chao, P.-D. L. (2014). Tissue distribution
AC

1064 of naringenin conjugated metabolites following repeated dosing of naringin to rats.

1065 BioMedicine, 4, 16.

1066 Liu, Y., An, W., & Gao, A. (2016). Protective effects of naringenin in cardiorenal syndrome.

1067 Journal of Surgical Research, 203, 416-423.

47
 ACCEPTED MANUSCRIPT

1068 Lonn, E., Bosch, J., Yusuf, S., Sheridan, P., Pogue, J., Arnold, J. M., et al. (2005). Effects of

1069 long-term vitamin E supplementation on cardiovascular events and cancer: a

1070 randomized controlled trial. JAMA, 293, 1338-1347.

1071 Lou, H., Jing, X., Wei, X., Shi, H., Ren, D., & Zhang, X. (2014). Naringenin protects against

PT
1072 6-OHDA-induced neurotoxicity via activation of the Nrf2/ARE signaling pathway.

RI
1073 Neuropharmacology, 79, 380-388.

1074 Luengo, E., Álvarez, I., & Raso, J. (2013). Improving the pressing extraction of polyphenols

SC
1075 of orange peel by pulsed electric fields. Innovative Food Science & Emerging

1076 Technologies, 17, 79-84.

1077
U
Manach, C., Morand, C., Gil-Izquierdo, A., Bouteloup-Demange, C., & Remesy, C. (2003).
AN
1078 Bioavailability in humans of the flavanones hesperidin and narirutin after the

ingestion of two doses of orange juice. European Journal of Clinical Nutrition, 57,
M

1079

1080 235-242.
D

1081 Manchope, M. F., Calixto-Campos, C., Coelho-Silva, L., Zarpelon, A. C., Pinho-Ribeiro, F.
TE

1082 A., Georgetti, S. R., et al. (2016). Naringenin Inhibits Superoxide Anion-Induced

1083 Inflammatory Pain: Role of Oxidative Stress, Cytokines, Nrf-2 and the NO-cGMP-
EP

1084 PKG-KATP Channel Signaling Pathway. PLoS One, 11, 153015.

1085 Martens, S., & Mithöfer, A. (2005). Flavones and flavone synthases. Phytochemistry, 66,
C

1086 2399-2407.
AC

1087 Martin, K., & Appel, C. (2009). Polyphenols as dietary supplements: A double-edged sword.

1088 Nutrition and Dietary Supplements, 2, 1-12.

1089 Martinez, R. M., Pinho-Ribeiro, F. A., Steffen, V. S., Caviglione, C. V., Vignoli, J. A.,

1090 Barbosa, D. S., et al. (2015). Naringenin Inhibits UVB Irradiation-Induced

48
 ACCEPTED MANUSCRIPT

1091 Inflammation and Oxidative Stress in the Skin of Hairless Mice. Journal of Natural

1092 Products, 78, 1647-1655.

1093 Martinez, R. M., Pinho-Ribeiro, F. A., Steffen, V. S., Silva, T. C., Caviglione, C. V., Bottura,

1094 C., et al. (2016). Topical Formulation Containing Naringenin: Efficacy against

PT
1095 Ultraviolet B Irradiation-Induced Skin Inflammation and Oxidative Stress in Mice.

RI
1096 PLoS One, 11, 146296.

1097 Mennen, L., Sapinho, D., Ito, H., Galan, P., Hercberg, S., & Scalbert, A. (2008). Urinary

SC
1098 excretion of 13 dietary flavonoids and phenolic acids in free-living healthy subjects–

1099 variability and possible use as biomarkers of polyphenol intake. European Journal of

1100 Clinical Nutrition, 62, 519-525.

U
AN
1101 Mershiba, S. D., Dassprakash, M. V., & Saraswathy, S. D. (2013). Protective effect of

naringenin on hepatic and renal dysfunction and oxidative stress in arsenic

M

1102

1103 intoxicated rats. Molecular Biology Reports, 40, 3681-3691.

D

1104 Micek, A., Grosso, G., Polak, M., Kozakiewicz, K., Tykarski, A., Puch Walczak, A., et al.
TE

1105 (2017). Association between tea and coffee consumption and prevalence of metabolic

1106 syndrome in Poland - results from the WOBASZ II study (2013–2014). International
EP

1107 Journal of Food Sciences and Nutrition, 69, 358-368.

1108 Miler, M., Zivanovic, J., Ajdzanovic, V., Orescanin-Dusic, Z., Milenkovic, D., Konic-Ristic,
C

1109 A., et al. (2016). Citrus flavanones naringenin and hesperetin improve antioxidant
AC

1110 status and membrane lipid compositions in the liver of old-aged Wistar rats.

1111 Experimental gerontology, 84, 49-60.

49
 ACCEPTED MANUSCRIPT

1112 Milke, L., Aschenbrenner, J., Marienhagen, J., & Kallscheuer, N. (2018). Production of

1113 plant-derived polyphenols in microorganisms: current state and perspectives. Applied

1114 Microbiology and Biotechnology, 102, 1575-1585.

1115 Motawi, T. K., Teleb, Z. A., El-Boghdady, N. A., & Ibrahim, S. A. (2014). Effect of

PT
1116 simvastatin and naringenin coadministration on rat liver DNA fragmentation and

RI
1117 cytochrome P450 activity: an in vivo and in vitro study. Journal of Physiology and

1118 Biochemistry, 70, 225-237.

SC
1119 Mozumdar, A., & Liguori, G. (2011). Persistent Increase of Prevalence of Metabolic

1120 Syndrome Among U.S. Adults: NHANES III to NHANES 1999–2006. Diabetes

1121 Care, 34, 216-219.

U
AN
1122 Mulvihill, E. E., Allister, E. M., Sutherland, B. G., Telford, D. E., Sawyez, C. G., Edwards, J.

Y., et al. (2009). Naringenin prevents dyslipidemia, apolipoprotein B overproduction,

M

1123

1124 and hyperinsulinemia in LDL receptor-null mice with diet-induced insulin resistance.
D

1125 Diabetes, 58, 2198-2210.

TE

1126 Muthaiah, V. P., Venkitasamy, L., Michael, F. M., Chandrasekar, K., & Venkatachalam, S.

1127 (2013). Neuroprotective role of naringenin on carbaryl induced neurotoxicity in

EP

1128 mouse neuroblastoma cells. Journal of Pharmacology and Pharmacotherapeutics, 4,

1129 192-197.
C

1130 Nakamura, T., Terajima, T., Ogata, T., Ueno, K., Hashimoto, N., Ono, K., et al. (2006).
AC

1131 Establishment and pathophysiological characterization of type 2 diabetic mouse

1132 model produced by streptozotocin and nicotinamide. Biological and Pharmaceutical

1133 Bulletin, 29, 1167-1174.

50
 ACCEPTED MANUSCRIPT

1134 Niyogi, M. (2016). Polyphenols in a vegetarian diet. The American Journal of Clinical

1135 Nutrition, 6, 113-116.

1136 Oboh, G., Nwokocha, K. E., Akinyemi, A. J., & Ademiluyi, A. O. (2014). Inhibitory effect of

1137 polyphenolic–rich extract from Cola nitida (Kolanut) seed on key enzyme linked to

PT
1138 type 2 diabetes and Fe2+ induced lipid peroxidation in rat pancreas in vitro. Asian

RI
1139 Pacific Journal of Tropical Biomedicine, 4, 405-412.

1140 Orsolic, N., Gajski, G., Garaj-Vrhovac, V., Dikic, D., Prskalo, Z. S., & Sirovina, D. (2011).

SC
1141 DNA-protective effects of quercetin or naringenin in alloxan-induced diabetic mice.

1142 European Journal of Pharmacology, 656, 110-118.

1143
U
Orsolic, N., Goluza, E., Dikic, D., Lisicic, D., Sasilo, K., Rodak, E., et al. (2014). Role of
AN
1144 flavonoids on oxidative stress and mineral contents in the retinoic acid-induced bone

loss model of rat. European Journal of Nutrition, 53, 1217-1227.

M

1145

1146 Ozkaya, A., Sahin, Z., Dag, U., & Ozkaraca, M. (2016). Effects of Naringenin on Oxidative
D

1147 Stress and Histopathological Changes in the Liver of Lead Acetate Administered
TE

1148 Rats. Journal of Biochemical and Molecular Toxicology, 30, 243-248.

1149 Palmer, B.F. (2004). Managing Hyperkalemia Caused by Inhibitors of the Renin-
EP

1150 Angiotensin-Aldosterone System. New England Journal of Medicine, 351, 585-592.

1151 Pari, L., & Gnanasoundari, M. (2006). Influence of Naringenin on Oxytetracycline Mediated
C

1152 Oxidative Damage in Rat Liver. Basic & Clinical Pharmacology & Toxicology, 98,
AC

1153 456-461.

1154 Parmar, N. S. (1983). The gastric anti-ulcer activity of naringenin, a specific histidine

1155 decarboxylase inhibitor. International journal of tissue reactions, 5, 415-420.

51
 ACCEPTED MANUSCRIPT

1156 Peng, H., Cheng, F., Huang, Y., Chen, C., & Tsai, T. (1998). Determination of naringenin

1157 and its glucuronide conjugate in rat plasma and brain tissue by high-performance

1158 liquid chromatography. Journal of Chromatography B: Biomedical Sciences and

1159 Applications, 714, 369-374.

PT
1160 Pereira-Caro, G., Polyviou, T., Ludwig, I. A., Nastase, A. M., Moreno-Rojas, J. M., Garcia,

RI
1161 A. L., et al. (2017). Bioavailability of orange juice (poly) phenols: the impact of

1162 short-term cessation of training by male endurance athletes. The American Journal of

SC
1163 Clinical Nutrition, 106, 791-800.

1164 Pinho-Ribeiro, F. A., Zarpelon, A. C., Fattori, V., Manchope, M. F., Mizokami, S. S.,

1165
U
Casagrande, R., et al. (2016b). Naringenin reduces inflammatory pain in mice.
AN
1166 Neuropharmacology, 105, 508-519.

Pinho-Ribeiro, F. A., Zarpelon, A. C., Mizokami, S. S., Borghi, S. M., Bordignon, J., Silva,
M

1167

1168 R. L., et al. (2016a). The citrus flavonone naringenin reduces lipopolysaccharide-
D

1169 induced inflammatory pain and leukocyte recruitment by inhibiting NF-kB activation.
TE

1170 Journal of Nutritional Biochemistry, 33, 8-14.

1171 Podder, B., Song, H. Y., & Kim, Y. S. (2014). Naringenin exerts cytoprotective effect against
EP

1172 paraquat-induced toxicity in human bronchial epithelial BEAS-2B cells through

1173 NRF2 activation. Journal of Microbiology and Biotechnology, 24, 605-613.

C

1174 Rahigude, A., Bhutada, P., Kaulaskar, S., Aswar, M., & Otari, K. (2012). Participation of
AC

1175 antioxidant and cholinergic system in protective effect of naringenin against type-2

1176 diabetes-induced memory dysfunction in rats. Neuroscience, 226, 62-72.

1177 Ramos-Escudero, F., Muñoz, A. M., Alvarado-Ortíz, C., Alvarado, A., & Yánez, J. A.

1178 (2012). Purple corn (Zea mays L.) phenolic compounds profile and its assessment as

52
 ACCEPTED MANUSCRIPT

1179 an agent against oxidative stress in isolated mouse organs. Journal of Medicinal

1180 Food, 15, 206-215.

1181 Ramprasath, T., Senthamizharasi, M., Vasudevan, V., Sasikumar, S., Yuvaraj, S., & Selvam,

1182 G. S. (2014). Naringenin confers protection against oxidative stress through

PT
1183 upregulation of Nrf2 target genes in cardiomyoblast cells. Journal of Physiology and

RI
1184 Biochemistry, 70, 407-415.

1185 Ranasinghe, P., Mathangasinghe, Y., Jayawardena, R., Hills, A. P., & Misra, A. (2017).

SC
1186 Prevalence and trends of metabolic syndrome among adults in the asia-pacific region:

1187 a systematic review. BMC Public Health, 17, 101.

1188
U
Raza, S. S., Khan, M. M., Ahmad, A., Ashafaq, M., Islam, F., Wagner, A. P., et al. (2013).
AN
1189 Neuroprotective effect of naringenin is mediated through suppression of NF-kB

signaling pathway in experimental stroke. Neuroscience, 230, 157-171.

M

1190

1191 Ren, B., Qin, W., Wu, F., Wang, S., Pan, C., Wang, L., et al. (2016). Apigenin and
D

1192 naringenin regulate glucose and lipid metabolism, and ameliorate vascular
TE

1193 dysfunction in type 2 diabetic rats. European journal of pharmacology, 773, 13-23.

1194 Rendeiro, C., Dong, H., Saunders, C., Harkness, L., Blaze, M., Hou, Y., et al. (2016).
EP

1195 Flavanone-rich citrus beverages counteract the transient decline in postprandial

1196 endothelial function in humans: a randomised, controlled, double-masked, cross-over

C

1197 intervention study. British Journal of Nutrition, 116, 1999-2010.

AC

1198 Renugadevi, J., & Prabu, S. M. (2009). Naringenin protects against cadmium-induced

1199 oxidative renal dysfunction in rats. Toxicology, 256, 128-134.

53
 ACCEPTED MANUSCRIPT

1200 Renugadevi, J., & Prabu, S. M. (2010). Cadmium-induced hepatotoxicity in rats and the

1201 protective effect of naringenin. Experimental and Toxicologic Pathology, 62, 171-

1202 181.

1203 Richard, A. J., Amini-Vaughan, Z., Ribnicky, D. M., & Stephens, J. M. (2013). Naringenin

PT
1204 inhibits adipogenesis and reduces insulin sensitivity and adiponectin expression in

RI
1205 adipocytes. Evidence-Based Complementary and Alternative Medicine, 2013,

1206 549750.

SC
1207 Roy, A., Das, A., Das, R., Haldar, S., Bhattacharya, S., & Haldar, P. K. (2014). Naringenin, a

1208 citrus flavonoid, ameliorates arsenic-induced toxicity in Swiss albino mice. Journal of

1209
U
Environmental Pathology, Toxicology and Oncology, 33, 195-204.
AN
1210 Roy, S., Ahmed, F., Banerjee, S., & Saha, U. (2016). Naringenin ameliorates streptozotocin-

induced diabetic rat renal impairment by downregulation of TGF-β1 and IL-1 via
M

1211

1212 modulation of oxidative stress correlates with decreased apoptotic events.

D

1213 Pharmaceutical biology, 54, 1616-1627.

TE

1214 Sachdeva, S., & Flora, S. J. (2014). Efficacy of some antioxidants supplementation in

1215 reducing oxidative stress post sodium tungstate exposure in male wistar rats. Journal
EP

1216 of Trace Elements in Medicine and Biology, 28, 233-239.

1217 Sachdeva, S., Pant, S. C., Kushwaha, P., Bhargava, R., & Flora, S. J. (2015). Sodium
C

1218 tungstate induced neurological alterations in rat brain regions and their response to
AC

1219 antioxidants. Food and Chemical Toxicology, 82, 64-71.

1220 Sahin, Z., Ozkaya, A., Cuce, G., Uckun, M., & Yologlu, E. (2017). Investigation of the effect

1221 of naringenin on oxidative stress-related alterations in testis of hydrogen peroxide-

1222 administered rats. Journal of Biochemical and Molecular Toxicology, 31.

54
 ACCEPTED MANUSCRIPT

1223 Saleh, T. M., Saleh, M. C., Connell, B. J., & Song, Y. H. (2017). A co-drug conjugate of

1224 naringenin and lipoic acid mediates neuroprotection in a rat model of oxidative stress.

1225 Clinical and Experimental Pharmacology and Physiology, 44, 1008-1016.

1226 Sarkar, A., Angeline, M. S., Anand, K., Ambasta, R. K., & Kumar, P. (2012). Naringenin and

PT
1227 quercetin reverse the effect of hypobaric hypoxia and elicit neuroprotective response

RI
1228 in the murine model. Brain Research, 24, 59-70.

1229 Serra, H., Mendes, T., Bronze, M., & Simplício, A. L. (2008). Prediction of intestinal

SC
1230 absorption and metabolism of pharmacologically active flavones and flavanones.

1231 Bioorganic & medicinal chemistry, 16, 4009-4018.

1232
U
Sesso, H. D., Buring, J. E., Christen, W. G., Kurth, T., Belanger, C., MacFadyen, J., et al.
AN
1233 (2008). Vitamins E and C in the prevention of cardiovascular disease in men: the

Physicians' Health Study II randomized controlled trial. JAMA, 300, 2123-2133.

M

1234

1235 Shimizu, T., Lin, F., Hasegawa, M., Okada, K., Nojiri, H., & Yamane, H. (2012).
D

1236 Purification and Identification of Naringenin 7-O-Methyltransferase, a Key Enzyme

TE

1237 in Biosynthesis of Flavonoid Phytoalexin Sakuranetin in Rice. The Journal of

1238 Biological Chemistry, 287, 19315-19325.

EP

1239 Silberberg, M., Gil-Izquierdo, A., Combaret, L., Remesy, C., Scalbert, A., & Morand, C.

1240 (2006). Flavanone metabolism in healthy and tumor-bearing rats. Biomedicine &
C

1241 Pharmacotherapy, 60, 529-535.

AC

1242 Sirovina, D., Orsolic, N., Gregorovic, G., & Koncic, M. Z. (2016). Naringenin ameliorates

1243 pathological changes in liver and kidney of diabetic mice: a preliminary study.

1244 Archives of Industrial Hygiene and Toxicology, 67, 19-24.

55
 ACCEPTED MANUSCRIPT

1245 Song, P., Yu, J., Chang, X., Wang, M., & An, L. (2017). Prevalence and Correlates of

1246 Metabolic Syndrome in Chinese Children: The China Health and Nutrition Survey.

1247 Nutrients, 9, 79.

1248 Soudani, N., Rafrafi, M., Ben Amara, I., Hakim, A., Troudi, A., Zeghal, K. M., et al. (2013).

PT
1249 Oxidative stress-related lung dysfunction by chromium (VI): alleviation by Citrus

RI
1250 aurantium L. Journal of Physiology and Biochemistry, 69, 239-253.

1251 Su, H. M., Feng, L. N., Zheng, X. D., & Chen, W. (2016). Myricetin protects against diet-

SC
1252 induced obesity and ameliorates oxidative stress in C57BL/6 mice. Journal of

1253 Zhejiang University SCIENCE B, 17, 437-446.

1254
U
Subburaman, S., Ganesan, K., & Ramachandran, M. (2014). Protective role of naringenin
AN
1255 against doxorubicin-induced cardiotoxicity in a rat model: histopathology and mRNA

expression profile studies. Journal of Environmental Pathology, Toxicology and

M

1256

1257 Oncology, 33, 363-376.

D

1258 Tsai, T.-H. (2002). Determination of naringin in rat blood, brain, liver, and bile using
TE

1259 microdialysis and its interaction with cyclosporin a, a p-glycoprotein modulator.

1260 Journal of Agricultural and Food Chemistry, 50, 6669-6674.

EP

1261 Tu, Y., Liu, F., Guo, D., Fan, L., Zhu, Z., Xue, Y., et al. (2016). Molecular characterization

1262 of flavanone 3-hydroxylase gene and flavonoid accumulation in two chemotyped

C

1263 safflower lines in response to methyl jasmonate stimulation. BMC Plant Biology, 16,
AC

1264 016-0813.

1265 Tundis, R., Loizzo, M. R., Menichini, F., Bonesi, M., & Colica, C. (2011). In vitro cytotoxic

1266 activity of extracts and isolated constituents of Salvia leriifolia Benth. against a panel

1267 of human cancer cell lines. Chemistry & Biodiversity, 8, 1152-1162.

56
 ACCEPTED MANUSCRIPT

1268 Van Hul, M., Geurts, L., Plovier, H., Druart, C., Everard, A., Stahlman, M., et al. (2017).

1269 Reduced obesity, diabetes and steatosis upon cinnamon and grape pomace are

1270 associated with changes in gut microbiota and markers of gut barrier. American

1271 Journal of Physiology. Endocrinology and Metabolism, 314, 334-352.

PT
1272 Wang, C., Fan, R. Q., Zhang, Y. X., Nie, H., & Li, K. (2016). Naringenin protects against

RI
1273 isoniazid- and rifampicin-induced apoptosis in hepatic injury. World Journal of

1274 Gastroenterology, 22, 9775-9783.

SC
1275 Wang, J., Yang, Z., Lin, L., Zhao, Z., Liu, Z., & Liu, X. (2012). Protective effect of

1276 naringenin against lead-induced oxidative stress in rats. Biological Trace Element

1277 Research, 146, 354-359.

U
AN
1278 Wang, K., Chen, Z., Huang, J., Huang, L., Luo, N., Liang, X., Liang, M., & Xie, W. (2017).

Naringenin prevents ischaemic stroke damage via anti-apoptotic and anti-oxidant

M

1279

1280 effects. Clinical and Experimental Pharmacology and Physiology, 44, 862-871.
D

1281 Wang, M.-J., Chao, P.-D. L., Hou, Y.-C., & Hsiu, S.-L. (2006). Pharmacokinetics and
TE

1282 conjugation metabolism of naringin and naringenin in rats after single dose and

1283 multiple dose administrations. Journal of Food and Drug Analysis, 14.
EP

1284 Wang, Q., Yang, J., Zhang, X.-M., Zhou, L., Liao, X.-L., & Yang, B. (2015). Practical

1285 synthesis of naringenin. Journal of Chemical Research, 39, 455-457.

C

1286 Wu, J., Zhou, T., Du, G., Zhou, J., & Chen, J. (2014). Modular optimization of heterologous
AC

1287 pathways for de novo synthesis of (2S)-naringenin in Escherichia coli. PLoS One, 9,

1288 101492.

1289 Wu, T., Tang, Q., Gao, Z., Yu, Z., Song, H., Zheng, X., & Chen, W. (2013). Blueberry and

1290 mulberry juice prevent obesity development in C57BL/6 mice. PLoS One, 8, 77585.

57
 ACCEPTED MANUSCRIPT

1291 Wu, T., Tang, Q., Yu, Z., Gao, Z., Hu, H., Chen, W., Zheng, X., & Yu, T. (2014). Inhibitory

1292 effects of sweet cherry anthocyanins on the obesity development in C57BL/6 mice.

1293 International Journal of Food Sciences and Nutrition, 65, 351-359.

1294 Wu, T., Yu, Z., Tang, Q., Song, H., Gao, Z., Chen, W., & Zheng, X. (2013). Honeysuckle

PT
1295 anthocyanin supplementation prevents diet-induced obesity in C57BL/6 mice. Food

RI
1296 & Function, 4, 1654-1661.

1297 Xi, B., He, D., Hu, Y., & Zhou, D. (2013). Prevalence of metabolic syndrome and its

SC
1298 influencing factors among the Chinese adults: The China Health and Nutrition Survey

1299 in 2009. Preventive medicine, 57, 867-871.

1300
U
Xie, L., Su, H., Sun, C., Zheng, X., & Chen, W. (2018). Recent advances in understanding
AN
1301 the anti-obesity activity of anthocyanins and their biosynthesis in microorganisms.

Trends in Food Science & Technology, 72, 13-24.

M

1302

1303 Xing, B.-h., Yang, F.-z., & Wu, X.-h. (2016). Naringenin enhances the efficacy of human
D

1304 embryonic stem cell-derived pancreatic endoderm in treating gestational diabetes

TE

1305 mellitus mice. Journal of Pharmacological Sciences, 131, 93-100.

1306 Xu, P., Ranganathan, S., Fowler, Z. L., Maranas, C. D., & Koffas, M. A. G. (2011). Genome-
EP

1307 scale metabolic network modeling results in minimal interventions that cooperatively

1308 force carbon flux towards malonyl-CoA. Metabolic Engineering, 13, 578-587.
C

1309 Yanez, J. A., Andrews, P. K., & Davies, N. M. (2007). Methods of analysis and separation of
AC

1310 chiral flavonoids. Journal of Chromatography B, 848, 159-181.

1311 Yen, F.-L., Wu, T.-H., Lin, L.-T., Cham, T.-M., & Lin, C.-C. (2009). Naringenin-loaded

1312 nanoparticles improve the physicochemical properties and the hepatoprotective

58
 ACCEPTED MANUSCRIPT

1313 effects of naringenin in orally-administered rats with CCl4-induced acute liver

1314 failure. Pharmaceutical research, 26, 893-902.

1315 Zamora-Ros, R., Rabassa, M., Cherubini, A., Urpi-Sarda, M., Bandinelli, S., Ferrucci, L., et

1316 al. (2013). High concentrations of a urinary biomarker of polyphenol intake are

PT
1317 associated with decreased mortality in older adults. The Journal of Nutrition, 143,

RI
1318 1445-1450.

1319 Zar Kalai, F., Han, J., Ksouri, R., El Omri, A., Abdelly, C., & Isoda, H. (2013). Antiobesity

SC
1320 Effects of an Edible Halophyte Nitraria retusa Forssk in 3T3-L1 Preadipocyte

1321 Differentiation and in C57B6J/L Mice Fed a High Fat Diet-Induced Obesity.

1322
U
Evidence-Based Complementary and Alternative Medicine, 2013, 368658.
AN
1323 Zeng, X., Su, W., Bai, Y., Chen, T., Yan, Z., Wang, J., et al. (2017). Urinary metabolite

profiling of flavonoids in Chinese volunteers after consumption of orange juice by

M

1324

1325 UFLC-Q-TOF-MS/MS. Journal of Chromatography B, 1061-1062, 79-88.

D

1326 Zhang, L., Xu, Y., Li, Y., Bao, T., Gowd, V., & Chen, W. (2017). Protective property of
TE

1327 mulberry digest against oxidative stress - A potential approach to ameliorate dietary

1328 acrylamide-induced cytotoxicity. Food Chemistry, 230, 306-315.

EP

1329 Zhang, P., Lin, R., Yang, G., Zhang, J., Zhou, L., & Liu, T. (2013). Solubility of Naringenin

1330 in Ethanol and Water Mixtures. Journal of Chemical & Engineering Data, 58, 2402-
C

1331 2404.
AC

1332 Zhang, X., Hu, S., Chen, F., & Wang, M. (2014). Treatment of proteins with dietary

1333 polyphenols lowers the formation of AGEs and AGE-induced toxicity. Food &

1334 Function, 5, 2656-2661.

59
 ACCEPTED MANUSCRIPT

1335 Zhang, Y., Liu, B., Chen, X., Zhang, N., Li, G., Zhang, L. H., & Tan, L. Y. (2017).

1336 Naringenin Ameliorates Behavioral Dysfunction and Neurological Deficits in a d-

1337 Galactose-Induced Aging Mouse Model Through Activation of PI3K/Akt/Nrf2

1338 Pathway. Rejuvenation Research, 20, 462-472.

PT
RI
U SC
AN
M
D
TE
C EP
AC

60
 ACCEPTED MANUSCRIPT

1339 Table. 1. Antioxidant, Anti-hyperlipidemic and Anti-obesity effect of Naringenin

1340
Antioxidant and free radical scavenging activity

PT
Source Compound/Extract and dose Model (in vitro/in vivo) Research Outcome Significance
Zea mays Methanol (80): water (20) Albino male mice • Reduced the MDA level and improved the endogenous Antioxidant activity (Ramos-
extract. Dose- 100 mg/mL antioxidant enzyme (CAT, TPX, and SOD). Escudero, Muñoz, Alvarado-

RI
(contain naringenin- 148 mg/kg Ortíz, Alvarado, & Yánez,
sample) 2012).
Xi’an Xiao Naringenin - (50 mg/kg) Lead (Pb)-induced adult • Improved the biochemical parameters, oxidative stress and Xeno-protective effect (Wang, et

SC
Cao Botanical male rats antioxidant enzyme (MDA, CAT, SOD, GSH, and GPX). al., 2012).
Development
Co., Ltd
Sigma-Aldrich Naringenin - (20 or 50 mg/kg) Arsenic (As)-induced • Improved the serum biomarkers and tissues oxidative Xeno-protective effect

U
adult male rats stress/antioxidant enzymes in a dose-dependent manner and (Mershiba, Dassprakash, &
restored the tissues histology. Saraswathy, 2013).

AN
Sigma-Aldrich Naringenin - (5 or 10 mg/kg) Arsenic (AS)-induced • Significantly normalized the body weights, organ weights, Xeno-protective effect (Roy, et
swiss albino mice hematological and serum biochemical profile, tissues oxidative al., 2014).
stress/antioxidant parameters, and DNA fragmentation.
Citrus Ethanolic extract - 100 and 300 Chromium (VI)-induced • Alleviated the oxidative stress/antioxidant enzyme profile of Xeno-protective effect (Soudani,

M
aurantium L. mg/kg (contain naringenin) female Wistar rats lung tissue and reformed the tissue histology. et al., 2013).
Sigma-Aldrich Naringenin (4 and 8 mg/kg) Cadmium (Cd)-induced • Significantly improved the body weights, organ weights, Xeno-protective effect (Das,
swiss albino mice hematological and serum biochemical profile, tissue oxidative Roy, Das, Bhattacharya, &

D
stress/antioxidant parameters. Haldar, 2016)
Solanum Naringenin (10 µM) UV light-induced human • Reduced the ROS formation, increased cell viability, carotenoid Photo-protective effect

TE
lycopersicum dermal fibroblasts (CCD- stability, and HO-1 expression. (Fernandez-Garcia, 2014)
1064Sk) cell line
Santa Cruz Naringenin (20, 30, 100 mg/kg) UVB irradiation-induced • Inhibited the skin edema, neutrophil recruitment, MMP-9 Photo-protective and anti-
Biotechnology hairless mice activity, pro-/anti-inflammatory cytokines, and oxidative stress inflammatory effect (Martinez,
EP
markers (O2•− production and gp91phox expression). et al., 2015).
Sigma-Aldrich Naringenin (100 mg/kg) Retinoic acid-induced • Improved the bone weight coefficient, bone length and Anti-osteoporosis effect
bone loss rats diameter, bone ash content, bone calcium and phosphorus (Orsolic, et al., 2014).
C

content.
Sigma-Aldrich Naringenin (50 mg/kg) Doxorubicin-induced • Improved the blood functional markers, tissues antioxidant Chemoprotective effect
AC

Naringenin-Oxime (20 and 40
mg/kg)
Sigma-Aldrich Naringenin - (50 mg/kg)
dalton’s lymphoma enzymes, histopathological changes, and tumor (Kathiresan, et al., 2016).
ascites (DLA) tumor- microenvironment.
bearing mouse
Cisplatin-induced Wistar • Restored the biochemical parameters, oxidative stress Chemoprotective effect
albino rats /antioxidant profile of serum and tissues; and reduced the DNA (Koyuncu, Kocyigit, Gonel,
damage markers (8-OHdG level, comet formation). Arslan, & Durgun, 2017).
Gentamycin-induced • Enhanced the audiological measurement (DPOAE and ABR), Anti-ototoxicity effect (Kocak,
adult male rats antioxidant and biochemical profiles, and cochleae histological. et al., 2017).

61
 ACCEPTED MANUSCRIPT

Source Compound/Extract and dose Model (in vitro /in vivo) Research Outcome Significance
Sigma-Aldrich Naringenin (100 mg/kg) Benzo[a]pyrene-induced • Reduced the oxidative stress markers, inflammatory markers, Antioxidant and anti-
male Wistar rats NF-kB and COX-2 expression. inflammatory effect (Ali, et al.,
• Improved the antioxidant enzymes activity and lung 2017).

PT
histological.
Naringenin (50 mg/kg) H2O2-induced male • Improved the testis weight, oxidative stress/antioxidant markers Antioxidant activity (Sahin,
Wistar rats (MDA, GSH, GST), and testis histology. Ozkaya, Cuce, Uckun, &

RI
Yologlu, 2017).
Sigma-Aldrich Naringenin (5 - 100 µM) Paraquat-induced human • Reduced the intracellular ROS production, upregulated the Cytoprotective effect (Podder,
bronchial epithelial antioxidant-related genes expression, induced the NRF2 Song, & Kim, 2014)
(BEAS-2B) cell line expression and its target genes (HO-1 and NQO1).

SC
Naringenin (0.30 mM) Sodium tungstate- • Improved the blood δ-aminolevulinic acid dehydratase (ALAD) Xeno-protective effect
exposed male Wistar rats activity, oxidative stress and antioxidant markers (blood, liver (Sachdeva & Flora, 2014)
and spleen tissue).

U
Anti-hyperlipidemic and anti-obesity effect

AN
Source Compound/Extract and dose Model (in vitro /in vivo) Research Outcome Significance
Sigma-Aldrich Experimental diet (naringenin - Male Sprague-Dawley • Decreased the plasma and hepatic cholesterol content, fecal Hypolipidemic effect (Lee, et al.,
0.1%) rats neutral sterols, and inhibited the HMG-CoA reductase and 1999).

M
ACAT activities.
Naringenin (1 and 3%) High fat fed –induced • Improved the hepatic fatty acid oxidation, insulin sensitivity, Hypolipidemic effect (Mulvihill,
LDL receptor null (Ldr(- et al., 2009)

D
and glucose tolerance. Decreased the hepatic cholesterol,
/-)) and C57BL/6J mice cholesterol ester synthesis, VLDL derived and endogenous fatty
acids.

TE
Sigma-Aldrich Naringenin - 3% High- /low-cholesterol- • Improved dyslipidemia, insulin resistance, inflammation Anti-hyperlipidemic and anti-
induced male (Ldr(-/-)) associated with obesity and atherosclerosis disease. inflammatory activity (Assini, et
mice al., 2013).
• Reduced the plasma, liver, and adipose tissue lipid profile,
EP
Naringenin doses - 0.003, High fat diet-induced Hypolipidemic and anti-
0.006, and 0.012 % in male long-evans hooded • Upregulated the fatty acid oxidation-related genes expression adiposity effects (Cho, Kim,
experimental diet. rats (PPAR-α, CPT-1 and UCP2). Andrade, Burgess, & Kim,
2011).
C

Naringenin (10 mg/kg) High fat diet-induced • Improved the serum and hepatic lipid metabolism, lipolysis and Anti-obesity effect (Zar Kalai, et
obese mice lipogenesis-related gene expression. al., 2013).
AC

Sigma-Aldrich Naringenin (6-50 g/mL) 3T3-L1 cell line • Decreased the lipid accumulation, and protein expression of Anti-adipogenic effect (Richard,
adipocyte (aP2, ADPN, PPAR , STAT5A). Amini-Vaughan, Ribnicky, &
Stephens, 2013).
1341
1342
1343

62

1344 Table. 2. Antidiabetic and Anti-inflammatory effect of Naringenin
1345
Source Compound/Extract and dose
Acalypha Aqueous extract, doses-100,
wilkesiana 200 and 300 mg/kg
(naringenin-11.12%)
Sigma-Aldrich Naringenin (50 mg/kg)
Naringenin (5 µg)
Sigma-Aldrich Naringenin (50 mg/kg)
Sigma-Aldrich naringenin (5 and 10 mg/kg)
Sigma-Aldrich Naringenin (50 mg/kg)
Sigma-Aldrich Naringenin (50 mg/kg)
SRL, India Naringenin (25, 50 mg/kg)
Sigma-Aldrich Naringenin (25 and 50 mg/kg)
AC
Naringenin (50 mg/kg)
Naringenin (50 or 100 mg/kg)
ACCEPTED MANUSCRIPT
Anti-hyperglycemic and antidiabetic effect
PT
Model (in vitro /in vivo) Research Outcome Significance
Alloxan-induced diabetic • Reduced the hyperglycemia and ocular oxidative stress markers. Retino- /Cardio-protective
rats • Improved the lipid profile, hepato-specific profile, electrolyte effects (Ikewuchi, Onyeike,
RI
profile, atherogenic index, and hematological markers. Uwakwe, & Ikewuchi, 2011).
Alloxan-induced diabetic • Improved the body weight, blood hematological and Anti-genotoxic effect (Orsolic,
mice immunological parameters, and peripheral lymphocytes DNA et al., 2011).
SC
damage.
Glucose-induced primary • Improved the cell viability, intracellular antioxidant profile. Anti-apoptosis effect (Kapoor,
hepatocyte (Rats) • Reduced the ROS generation, Cyt-c and AIF/Endo-G Rizvi, & Kakkar, 2013).
translocation, caspase-9/-3 activation, Bcl-2 family genes
U
expression, DNA damage and chromatin condensation.
Streptozotocin-induced • Alleviated the ROS generation, oxidative stress parameters, liver Anti-apoptosis effect (Kapoor, &
AN
diabetes rats and kidney biomarkers, mitochondrial membrane dysfunction, and Kakkar, 2014).
apoptotic proteins expression of liver tissue.
Streptozotocin-induced • Reduced the biochemical and oxidative stress parameters, renal Nephroprotective effect (Roy,
M
diabetes rats degradation, TGF-β1 and IL-1 upregulation, and kidney apoptosis. Ahmed, Banerjee, & Saha,
2016).
Alloxan-induced diabetic • Restore the diabetics induced the hepatic and renal pathological Hepato- /reno-protective effect
mice (Sirovina, Oršolić, Gregorović,
D
changes.
& Končić, 2016)
Streptozotocin– • Significantly lowered the blood glucose and glycosylated Anti-hyperglycemic and
TE
nicotinamide-induced hemoglobin; improved the serum insulin, plasma, and pancreatic antioxidant activity (Annadurai,
diabetic rats tissue antioxidants enzyme; restore the pancreatic histology. et al., 2012).
High-fat diet /high fat • Improved the body weight and blood glucose, MDA, nitric oxide Neuro-protective effect
EP
emulsion with and reduced glutathione levels. (Rahigude, Bhutada, Kaulaskar,
streptozotocin-induced • Reduced the locomotor activity and inhibited the cholinesterase Aswar, & Otari, 2012).
T2D rats activity.
Streptozotocin-induced • Lessened the serum glucose, pro-inflammatory cytokines, nitric Neuro-protective effects (Al-
C
diabetic rats oxide production, oxidative stress marker (MDA); improved the Rejaie, et al., 2015).
insulin levels, antioxidant enzyme activity, insulin growth factor
(IGF) and nerve growth factor (NGF) expression of the sciatic
nerve, and sciatic nerve histology.
Streptozotocin-induced • Ameliorated the hyperglycemia, oxidative stress/antioxidant Retino-protective effect (Al-
diabetic rats markers, apoptosis markers (Bax/Bcl2, caspase-3), and Dosari, Ahmed, Al-Rejaie,
neuroprotective factors (Brain-derived neurotrophic factor, Alhomida, & Ola, 2017).
tropomyosin-related kinase B, and synaptophysin).
High-fat diet • Ameliorated the glucose and lipid metabolism, insulin resistance, Anti-vasculopathy effect (Ren,
63
 ACCEPTED MANUSCRIPT
Source Compound/Extract and dose Model (in vitro /in vivo)
/streptozotocin-induced
diabetic rats
Cola nitida Naringenin content- 3.6% In-vitro
Naringenin (50 mg/kg) Pancreatic endoderm
derived from human
embryonic stem cells
(hESCs)
Anti-inflammatory effect
Source Compound/Extract and dose Model (in vitro /in vivo)
Naringenin (25, 50, and 100 Acetic acid-induced rats
mg/kg)
Sigma-Aldrich Naringenin (50 mg/kg) High-cholesterol fed rats
D
Sigma-Aldrich Naringenin (50 and 100 mg/kg) Lipopolysaccharide
(LPS)-induced rats
TE
Santa Naringenin (16.7, 50, and 150 Superoxide anion (KO2)-
Cruz mg/kg) induced mice
EP
Biotechnology
C
Naringenin (50 mg/kg) Lipopolysaccharide
(LPS)- induced mice
AC
Naringenin (50 mg/kg) Indomethacin-induced
mice
Santa Naringenin (0.5%) Ultraviolet B irradiation-
Research Outcome Significance
oxidative stress and inflammation markers, and thoracic aorta's et al., 2016).
pathology.
• Inhibited the α-amylase and α-glucosidase enzyme activity and In-vitro anti-diabetic activity
PT
reduced the pancreatic MDA level. (Oboh, Nwokocha, Akinyemi, &
Ademiluyi, 2014).
• Improved the body weight, blood glucose, and insulin level, Anti-diabetic activity (Xing,
oxidative stress/antioxidant markers, reproductive outcome. Yang, & Wu, 2016).
RI
SC
Research Outcome Significance
U
• Significantly reduced the colon weight/length, colon histological Antioxidant and anti-
changes, oxidative stress, inflammatory protein; increased the inflammatory effects (Al-Rejaie,
AN
mucosal content, antioxidant profile (T-GSH, NPSH, SOD, CAT), et al., 2013).
nucleic acids concentrations (DNA, RNA, total protein).
• Improved the hematological parameters, lipid profile, renal Anti-inflammatory and anti-
aggregate activity (Chtourou, et
M
oxidative stress-related markers, renal histology, mRNA
expression of kidney and platelets membrane (Ecto-nucleotide al., 2016).
triphosphate diphosphohydrolases (NTPDases), ecto-5’-
nucleotidase (CD73), iNOS, TNF-α, IL-6, and NF-κB).
• Reduced the wet/dry lung weight ratio, tissue biochemical profile Antioxidant, Anti-inflammatory,
(MDA, NO, IL-6, MPO), lung histological damage, lung immune- anti-nitrosative, and anti-
histochemical expression (NF-κB, iNOS, TNF-α, caspase-3, and apoptotic effect (Fouad, Albuali,
HSP70). & Jresat, 2016).
• Reduced the pain like behavior, mechanical hyperalgesia, thermal Anti-nociceptive, anti-
hyperalgesia, MPO activity, oxidative stress-related markers, and inflammatory effect (Manchope,
cytokine production (IL-33, IL-10, and TNF- α); and activated the et al., 2016).
NO-cGMP-PKG-KATP channel and related Nrf2/HO-1 signaling
pathway.
• Reduced the pain like behavior, mechanical hyperalgesia, thermal Anti-nociceptive, anti-
hyperalgesia, MPO activity, oxidative stress-related markers, and inflammatory effect (Pinho-
cytokine production in the paw skin. Naringenin also the reduced Ribeiro, et al., 2016a).
leukocyte recruitment, MPO and NAG activity, cytokine and
superoxide anion production, and LPO in the peritoneal cavity.
• Inhibited the oxidative stress, NF-kB activation, hyperalgesic Anti-nociceptive, anti-
cytokine production, neutrophil recruitment, and NO-cyclic GMP- inflammatory effect (Pinho-
PKG-ATP sensitive K+ channel pathway activation. Ribeiro, et al., 2016b).
• Reduced the skin edema, superoxide anion and lipid Anti-inflammatory and anti-
hydroperoxides production, inflammatory cytokines (TNF-α, IL-
64
 ACCEPTED MANUSCRIPT

Source Compound/Extract and dose Model (in vitro /in vivo) Research Outcome Significance

Cruz induced hairless mice 1β, IL-6, and IL-10). Improved the mRNA expression of GPx-1, GR, oxidative stress activity
Biotechnology Nrf2, and HO-1. (Martinez, et al., 2016).
Sigma-Aldrich Naringenin (25, 50, and 100 Thermal burn-induced • Reduced the pro-inflammatory cytokines (TNF- α, IL-1 β, IL-6), Anti-inflammatory and

PT
mg/kg) rats inflammatory markers (NO, PGE2, Caspase-3, LT-B4, and NF- antioxidant effects (Al-
kB), oxidative stress parameters, and dermal histological changes. Roujayee, 2017).
Naringenin (50, 100 or 200 Pemphigus vulgaris- • Improved the cellular apoptosis, antioxidant activity, cell-cell Antioxidant, anti-inflammatory

RI
µM) treated HaCaT cell line contacts disruption (cell fragments), ROS generation and and anti-apoptosis effects
mitochondrial transmembrane potential, keratinocyte adhesion (Liang, et al., 2017).
molecules (Dsg1, Dsg3, and E-cadherin) and NOD2- mediated NF-

SC
kB pathway expression (NOD2, RIPK2, and NF-kB p-p65).
1346
1347

U
1348
1349

AN
1350
1351

M
1352
1353
1354

D
1355
1356

TE
1357
1358
EP
1359
1360
1361
C

1362
1363
AC

1364
1365
1366
1367
1368
1369
65
 ACCEPTED MANUSCRIPT

1370 Table. 3. Organo-protective effects of Naringenin

1371
Hepato- and reno-protective effect

PT
Source Compound/Extract and dose Model (in vitro /in vivo) Research Outcome Significance
Sigma-Aldrich Naringenin (50 mg/kg) Oxytetracycline-induce • Ameliorated the hepato-specific biochemical profile (AST, ALT, Hepatoprotective effect (Pari &
rats ALP, LDH), bilirubin), oxidative stress profile (TBARS, lipid Gnanasoundari, 2006).

RI
hydroperoxides), antioxidant profile (Vit-C and -E, GSH, SOD,
CAT, GPx), and histological damage.
Sigma-Aldrich Naringenin (50 mg/kg) Ethanol-induced • Significantly improved the biochemical parameters, oxidative Hepatoprotective effect

SC
hepatotoxicity stress/antioxidant markers, and histopathological changes. (Jayaraman, Veerappan, &
Namasivayam, 2009).
Sigma-Aldrich Naringenin (100 mg/kg) Carbon tetrachloride- • Reduced the hepatic biochemical parameters, oxidative stress Hepatoprotective effect (Yen,
induced rats markers, apoptosis markers (caspase-3, -8, and -9). Wu, Lin, Cham, & Lin, 2009).

U
Sigma-Aldrich Naringenin (50 mg/kg) Carbon tetrachloride- • Reduced the hepatic biochemical parameters, oxidative stress Anti-inflammatory and anti-
induced rats markers, pro-inflammatory protein (iNOS, COX-2, and TNF-α). hepatotoxic effect (Esmaeili, &

AN
• Upregulated the anti-oxidative defense protein (HO-1 and Nrf-2). Alilou, 2014).
Sigma-Aldrich Naringenin (50 mg/kg) Cadmium (Cd)-induced • Ameliorated the biochemical profile (AST, ALT, ALP, LDH, Hepatoprotective effect
rats GGT, and TB), oxidative stress profile (TBARS, lipid (Renugadevi & Prabu, 2010).
hydroperoxides), antioxidant profile (Vit-C and -E, GSH, SOD,

M
CAT, GPx), and histological damage.
Sigma-Aldrich Naringenin (50 mg/kg) Arsenic (As)-induced • Increased the antioxidant profile (GSH, SOD, and CAT) and Hepatoprotective effect (Jain,
rats decreased the oxidative stress profile (GST and TBARS). Yadav, Bozhkov, Padalko, &

D
Flora, 2011)
Merck KGaA Naringenin (50 mg/kg) Lead (Pb)-induced rats • Increased the antioxidant profile and decreased the oxidative Hepatoprotective effect

TE
stress profile. (Ozkaya, Sahin, Dag, &
Ozkaraca, 2016)
Sigma-Aldrich Naringenin (15 mg/kg) Old-aged Wistar rats • Improved the hepatic antioxidant status (SOD 1/2, GPx, GR, and Hepatoprotective effect (Miler,
GSH), membrane phospholipid composition (of n-3 PUFA and n- et al., 2016).
EP
6/n-3 PUFA ratio).
• Significantly decreased the TBARS without affecting serum
biochemical (AST, ALT), and liver histology.
C

Sigma-Aldrich Naringenin (50 mg/kg) Cholesterol-induced rats • Lowered the plasma lipid profile, oxidative stress profile, Hypolipidemic, anti-
inflammatory markers (iNOS, Emr1, TNF-α, IL-1 β, IL-6, and inflammatory and anti-
AC

NF-κB), ECM dysregulation (matrix metalloproteinases (MMP) - hepatotoxic effect (Chtourou, et

2/-9 expression and proMMP-9/-2 activities), DNA al., 2015).
fragmentation, and histological damage.
Alfa Aesar Naringenin (50 mg/kg) Adult female Wistar • Significantly improved the liver function, oxidative stress Hepatoprotective effect
albino rats markers, DNA fragmentation, and histopathological changes. (Motawi, Teleb, El-Boghdady,
& Ibrahim, 2014)
Sigma-Aldrich Naringenin (50 and 100 mg/kg) Drugs (Isoniazid and • Improved the serum biochemical (AST, ALT), liver histology, Hepatoprotective effect (Wang,
rifampicin)-induced oxidative stress/anti-oxidant parameters (MDA, GSH, SOD), and Fan, Zhang, Nie, & Li, 2016).
66
 ACCEPTED MANUSCRIPT

Source Compound/Extract and dose Model (in vitro /in vivo) Research Outcome Significance
mice hepatocyte apoptosis (TUNEL assay).
Algerian propolis Ethanolic extract- 100 mg/kg Doxorubicin-induced • Significantly restored the kidney profile (serum creatinine, Reno-protective effects
(naringenin-14.27%) rats gamma-glutamyltranspeptidase enzyme activity) and oxidative (Boutabet, Kebsa, Alyane, &

PT
stress-related markers (MDA, GSH). Lahouel, 2011).
Sigma-Aldrich Naringenin (50 mg/kg) Carbon tetrachloride- • Reduced the renal oxidative stress-related markers (DA, SOD, Reno-protective effects
induced mice CAT, GPx, GSH) and pathohistological changes of kidney tissue. (Hermenean, et al., 2013).
Sigma-Aldrich Naringenin (50 mg/kg) Gentamicin-induced rats • Ameliorated the renal parameter (Creatinine), oxidative stress- Antioxidant, anti-inflammatory,

RI
related markers (MDA, GPx), inflammatory markers (NO and IL- and renoprotective effects
8). (Fouad, Albuali, Zahran, &
• Improved the renal histology, and the immunoreactivity Gomaa, 2014).

SC
(decreased the KIM-1, iNOS, VEGF, caspase-9, and increased
the surviving expression) of the renal tubular cells.
Sigma-Aldrich Naringenin (20 mg/kg) Daunorubicin-induced • Ameliorated the renal biochemical profile, histology, protein Anti-inflammatory, anti-
rats apoptosis, and reno-protective

U
expression of AT1R and ERK1/2-NFκB p65 signaling pathway,
ER stress and apoptosis, and inflammatory markers. effects (Karuppagounder, et al.,
2015).

AN
Anti-hypertensive and cardioprotective effect

Source Compound/Extract and dose Model (in vitro /in vivo) Research Outcome Significance

M
Dracocephalum Naringenin-7-O-glucoside (5- Doxorubicin-induced • Improved the cell viability, cellular morphological injury, Antioxidant, cardo-protective
rupestre 20 µM) cardiomyocytes (H9c2) intracellular ROS generation, extracellular LDH content, CK and anti-apoptosis effects (Han,

D
cell line level, cellular GSH-Px activity, and intracellular Ca2+ et al., 2012).
concentration.

TE
Sigma-Aldrich Naringenin (50 µM) H2O2-treated H9c2 cell • Improved the cell viability, oxidative stress-related parameters Antioxidant, cardo-protective
line (glutathione, MDA, NO, catalase, GSH-Px, and GST), and anti-inflammatory effects
transcription gene (Akt, NF-κB, and Caspase 3), and Nrf2/ARE (Ramprasath, et al., 2014).
signaling.
EP
Sigma-Aldrich Naringenin (25 and 50 mg/kg) Cardiorenal syndrome • Improved the lipid profile, cardiac inflammatory markers, Antioxidant, cardo-protective
rats oxidative stress parameters, and Nrf2/GCLc-regulated GSH and renoprotective effects (Liu,
synthesis. An, & Gao, 2016).
Sigma-Aldrich Naringenin (50 mg/kg) Doxorubicin-induced rat • Improved the body weight, heart weight, cardiac enzymes Antioxidant, cardo-protective
C

markers (LDH activity and troponin T (cTnT)), oxidative stress- and anti-inflammatory effects
(Subburaman, Ganesan, &
AC

related parameters (MDA, SOD, CAT, GPx), mRNA expression

of inflammatory markers (TGF-β1, TNF-α, IL-6, and IL-10), and Ramachandran, 2014).
heart architecture.
Sigma-Aldrich Naringenin (50 mg/kg) Cholesterol-induced rat • Reduced the relative heart weights (%), cardiac lipid profile, Antioxidant, cardio-protective
serum cardiac markers, antioxidant status, heart mitochondrial effects (Chtourou, Slima,
enzymes marker, cardiac cell death marker expression. Makni, Gdoura, & Fetoui,
• Improved the cardiac tissue histology. 2015).
Sigma-Aldrich Naringenin (40 µM) H2O2-induced H9c2 cell • Modulated the ROS levels, DNA damage, the mitochondrial Anti-aging and cardio-protective

67
 ACCEPTED MANUSCRIPT

Source Compound/Extract and dose Model (in vitro /in vivo) Research Outcome Significance
line potassium channels, mitochondrial oxidative metabolism activity, effects (Da Pozzo, et al., 2017).
estradiol level, and estrogen-related pathways (ER and VDR).
Sigma-Aldrich Naringenin (50 mg/kg) Monocrotaline-induced • Improved the body, heart and lung weights, heart rate, blood Anti-oxidant, anti-inflammation,

PT
pulmonary hypertensive pressure, electrocardiography, echocardiography. hypotensive, and anti-apoptosis
rats. • Ameliorated the oxidative stress-related markers, inflammatory effect (Ahmed, Obaid, Zaki, &
markers, nitric oxide synthase, total nitrate/nitrite (NOx) level, Agha, 2014).
apoptosis markers, tissues histological changes.

RI
Schinus Methanolic extract (30 mg/kg) Wistar rats and albino • Reduced blood pressure (Systolic, median, and diastolic), and Anti-oxidant and
terebinthifolius (contain naringenin) male mice relax the vasoconstriction antihypertensive effect (de Lima
Gloria, et al., 2017).

SC
Neuroprotective effect

Source Compound/Extract and dose Model (in vitro /in vivo) Research Outcome Significance

U
Sisco research Naringenin (25 and 50 mg/kg) Chronic construction • Attenuated the pain induced physical and behavioral changes Antioxidant and anti-

AN
Lab, India injury-induced rats (thermal hyperalgesia, cold allodynia, mechanical hyperalgesia, neuropathic pain effects
and foot deformity), oxidative stress markers (MDA, GSH, NO). (Kaulaskar, Bhutada, Rahigude,
Jain, & Harle, 2012).
Sigma-Aldrich Naringenin (50 mg/kg) Intracerebroventricular- • Improved the behavior change, spatial learning and memory, Neuroprotective effect (Khan, et

M
streptozotocin-induced choline acetyltransferase (ChAT) expression, and hippocampus al., 2012).
rats histology.
• Decrease the non-enzymatic parameters (4-HNE, MDA, TBARS,

D
H2O2, PC, and GSH), increase the enzymatic activity (GPx, GR,
GST, SOD, CAT, and Na+/K+- ATPase).
• Improved the behavioral change, hippocampus oxidative stress

TE
Sigma-Aldrich Naringenin (100 mg/kg) Beta-amyloid (Aβ)- Neuroprotective effect
induced rats markers (MDA, nitrate level, and SOD) and apoptosis (DNA (Ghofrani, et al., 2015).
fragmentation).
Sigma-Aldrich Naringenin (10 mg/kg) Hypoxia-induced swiss • Ameliorated the behavioral changes (poking and rearing Neuroprotective effect (Sarkar,
EP
albino mice behavior), neurological damage by altering the hypoxic brain, Angeline, Anand, Ambasta, &
protein, and immunoexpression of the cortex, stratum radiatum Kumar, 2012).
and hippocampus (VEGF, HIF1α, Hsp70, Hsp90, CHIP panel,
caspase-3, and ubiquitination).
C

Sigma-Aldrich Naringenin (100 µM) Carbaryl-induced mouse • Improved the cell viability, ROS generation, mitochondrial Neuroprotective effect
neuroblastoma cell line membrane potential, apoptotic genes expression (Bax/Bcl2, (Muthaiah, Venkitasamy,
AC

(Neuro 2A) caspase-3). Michael, Chandrasekar, &

Venkatachalam, 2013).
Sigma-Aldrich Naringenin (50 mg/kg) MCAO-induce focal • Improved the behavioral changes (neurological deficits, motor Anti-oxidant, anti-inflammatory
cerebral ischemia rats function, grip performance, and somatosensory deficit), and neuroprotective effect
upregulate the antioxidant profile, decreases the infarct size, ((Raza, et al., 2013).
lowered inflammatory parameters (MPO, NO, and cytokines),
and improved brain tissue protein and immunoexpression (SOD,

68
 ACCEPTED MANUSCRIPT

Source Compound/Extract and dose Model (in vitro /in vivo) Research Outcome Significance
NF-kB, iNOS, COX-2, and Iba-1).
Sigma-Aldrich Naringenin (50 mg/kg) Iron-induced cerebral • Suppressed the oxidative stress-related markers, antioxidant Anti-oxidant and neuro-
cortex neurotoxic rats enzyme activities, Na+/K+- ATPase and ChAT activity, DNA protective effect (Chtourou,

PT
fragmentation, and cerebral cortex histology. Fetoui, & Gdoura, 2014).
Sigma-Aldrich Naringenin (50 mg/kg) Iron-induced • Suppressed the behavioral changes (anxiety-like behavior, Anti-oxidant and neuro-
hippocampus neurotoxic locomotor activity and exploratory behavior, anxiolytic-like protective effect (Chtourou,
rats behavior), oxidative stress-related markers, antioxidant enzyme Slima, Gdoura, & Fetoui, 2015)

RI
activities, ectonucleotidase and ChAT activity.
Sigma-Aldrich Naringenin (0.30 mM) Tungsten (W)-induced • Improved the oxidative stress-related parameters (ROS level, Anti-oxidant and
rats MDA, GSH, GSSG, GPx), biogenic amines (dopamine, neuroprotective effect

Naringenin (70 mg/kg for in
vivo) and (40 and 80 µM for in
SC
norepinephrine, and 5-hydroxytryptamine), brain AChE and (Sachdeva, Pant, Kushwaha,
MAO activity. Bhargava, & Flora, 2015).
6-hydroxydopamine (6- • Improved the cell viability, LDH release, ROS production and Anti-oxidant, anti-apoptosis, and
OHDA)-induced human GSH level, Nrf2/ARE and JNK/p38 pathway, immunoreactivity neuro-protective effect (Lou, et

U
vitro) neuroblastoma cells line and protein expression of tyrosine hydroxylase (striatum and SNc al., 2014).
(SH-SY5Y) and mice section of the brain).

AN
model
Naringenin Oxygen and glucose • Improved the neuron cell proliferation, oxidative stress-related Anti-oxidant, anti-apoptosis, and
deprivation-cortical profile (ROS, MDA, and SOD), mitochondrial dysfunction, neuroprotective effect (Wang, et

Naringenin (50 mg/kg)
M
neuron cells and cerebral edema and neurological defects, Nrf2 protein regulation al., 2017).
neonatal Sprague- and translation, apoptosis markers (caspase -3/-9, Bax/Bcl2, and
Dawley rats DNA fragmentation).
D-galactose-induced • Improved the body weight and organ index, lessen the behavioral Anti-oxidant, anti-apoptosis, and

D
mice changes (locomotion, spatial learning, and memory performance), neuro-protective effect (Zhang,
restored the brain histopathological, reduced the neuronal loss et al., 2017).

TE
and apoptosis (TUNEL and Nissl staining of hippocampus and
cortex), oxidative stress-related markers, and PI3K/Akt/Nrf2
pathway.
EP
1372
C
AC

69
 ACCEPTED MANUSCRIPT

1373 Figure captions

1374

1375 Figure 1. Structure of naringenin and its analogs.

1376

PT
1377 Figure 2. Biological effects of naringenin.

RI
1378

1379 Figure 3. Major steps of naringenin production in plants. PAL, Phenyl-alanine ammonia lyase;

SC
1380 TAL, Tyrosine ammonia lyase; C4H, Cinnamate 4-hydroxylase; 4CL, 4-coumarate: CoA ligase;

1381 CHS, Chalcone synthase; CHI, Chalcone isomerase.

1382
U
AN
1383 Figure 4. Schematic overview of naringenin against metabolic diseases.

1384
M

1385
D

1386
TE

1387

1388
EP

1389

1390
C

1391
AC

1392

1393

1394

1395

70
 ACCEPTED MANUSCRIPT

1396

1397 Figure 1

PT
RI
U SC
AN
M
D
TE

1398
EP

1399

1400
C

1401
AC

1402

1403

1404

1405

1406
71
 ACCEPTED MANUSCRIPT

1407

1408 Figure 2

PT
RI
U SC
AN
M
D

1409
TE

1410

1411
EP

1412

1413
C

1414
AC

1415

1416

1417

1418

72
 ACCEPTED MANUSCRIPT

1419

1420 Figure 3

PT
RI
U SC
AN
M
D
TE
C EP

1421
AC

1422

1423

1424

1425

1426

73
 ACCEPTED MANUSCRIPT

1427

1428 Figure 4

PT
RI
U SC
AN
M
D
TE
EP

1429

1430
C

1431
AC

74
 ACCEPTED MANUSCRIPT

Highlights

• Naringenin exerts potential protective effect against metabolic disorder.

• Bioavailability and health effects of naringenin are discussed.

• Naringenin has the potential to be a dietary supplement against metabolic disease.

PT
• Potential sources of naringenin are summarized.

RI
U SC
AN
M
D
TE
C EP
AC