Articles Service
Review
A Comprehensive Review of Naringenin, a Promising Phytochemical with Therapeutic Potential
1Department of Food and Nutrition, Gyeongsang National University, Jinju 52828, Republic of Korea
2Department of Bio & Medical Bigdata (BK4 Program), Gyeongsang National University, Jinju 52828, Republic of Korea
J. Microbiol. Biotechnol. 2024; 34(12): 2425-2438
Published December 28, 2024 https://doi.org/10.4014/jmb.2410.10006
Copyright © The Korean Society for Microbiology and Biotechnology.
Abstract
Keywords
Graphical Abstract

Introduction
Advances in medical technology have increased human life expectancy; however, aging and westernized eating habits have led to the development of various diseases, including cancer, metabolic disorders, and neurodegenerative diseases. Cancer is one of the leading causes of death in humans, and its prevalence is expected to continue to increase, according to the World Health Organization (WHO) [1]. Cancer is treated by a combination of treatments, including surgery and chemotherapy; however, owing to the side effects, prevention through healthy eating is more essential [2, 3]. Furthermore, healthy eating habits are crucial in alleviating metabolic disorders, including obesity. Metabolic disorders can significantly lead to cardiovascular diseases and subsequent death [4]. Increased reactive oxygen species (ROS) due to aging can induce neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD) [5-7]. Prevention of neurodegenerative diseases is essential because the cure is impossible, and the cause remains unclear [8].
Polyphenols, which can be used as a solution for suppressing the onset of diseases, are naturally derived compounds with low toxicity and beneficial effects [9-11]. Polyphenols are abundant in vegetables and fruits and have antioxidant activity, showing beneficial effects in various diseases [12, 13]. Polyphenols include flavonoids and non-flavonoids [14]. Naringenin, a member of the flavonoid family, is a flavanone mainly noted in citrus fruits [15]. Naringenin has antioxidant, anti-inflammatory, and anti-viral effects and lowers the risk of cardiovascular disease, metabolic syndrome, and cancer [16].
We here comprehensively review the various effects of naringenin. First, we describe the sources of naringenin and its characteristics. Second, we discuss the pharmacokinetic aspects of naringenin and explain how it is absorbed, distributed, metabolized, and extracted in the body. Third, we discuss the effects of naringenin on cancer, metabolic disorders, and neurodegenerative diseases. Additionally, we summarize the inhibitory effects of naringenin on colorectal, gastric, lung, breast, ovarian, cervical, prostate, bladder, liver, pancreatic, and skin cancers. Diabetes, obesity, hyperlipidemia, hypertension, cardiac toxicity, hypertrophy, steatosis, liver disease, and arteriosclerosis are described in the metabolic disorder section. Finally, we here discuss the effects of naringenin on neurodegenerative diseases, including AD and PD.
Natural Sources of Naringenin
Naringenin ((2S)-5,7-dihydroxy-2-(4-hydroxyphenyl)-2,3-dihydrochromen-4-one) is a flavanone, a type of flavonoid, and is colorless and odorless (Fig. 1) [17, 18]. With a molecular weight of 272.256 g/mol and a melting point of 251°C, naringenin demonstrates favorable solubility in organic solvents, including ethanol, dimethylformamide, and dimethyl sulfoxide. Conversely, its solubility in buffered aqueous solutions is limited, reaching approximately 475 mg/l [19-21].
-
Fig. 1. The structure and natural sources of naringenin.
Naringenin is the most abundant in grapefruit, with a content of 53.00 mg/100 g. The contents of naringenin in other fruits are as follows: yuzu, 24.82mg/100g; pummelo, 24.72mg/100 g; orange, 15.32 mg/100 g; tangerine, 10.02 mg/100 g; and lime, 3.40 mg/100 g (Fig. 1) [22].
Moreover, in humans, the naringenin content is crucial owing to its conversion into naringenin by naringinase. This breakdown process occurs in two steps. First, naringinase exhibits α-L-rhamnosidase activity, thereby leading to naringin hydrolysis into rhamnose and prunin. Second, prunin is further hydrolyzed by the β-D-glucosidase activity of naringinase, subsequently forming naringenin and glucose [23].
Citrus fruits, such as musk lime, Mexican lime, rough lime, pummelo, and mandarin orange, are abundant in naringin, similar to naringenin. Pummelós peel (3,910 μg/g) contains more naringin content than its juice (220 μg/g). Similarly, the peel, juice, and seeds of rough lime have naringin contents of 517, 98, and 29 μg/g, respectively [24].
Pharmacokinetics of Naringenin
Absorption
Naringenin is absorbed in the duodenum, jejunum, ileum, cecum, and colon; however, its systemic absorption rate is limited [25, 26].
Studies conducted in human intestinal Caco-2 cells [27] have reported that naringenin is partially absorbed through passive diffusion, and pH changes do not affect its absorption. Furthermore, it has been identified as a substrate for adenosine triphosphate (ATP)-dependent transport facilitated by multidrug resistance-associated protein 1. Another study using a murine intestinal tract model [28] has shown that the highest absorption rate (68%) of naringenin occurred in the colon. The following were the absorption rates in different parts of the intestine: duodenum 47%; terminal ileum 42%; and jejunum 39%. Moreover, a pharmacokinetic study in humans [29] has noted the following parameters related to a 135-mg naringenin oral dose: area under the plasma concentration-time curve (AUC0-∞) of 9,424.52 ng h/mL; elimination half-life, 2.31 h; and relative cumulative urinary excretion, 5.81%.
Distribution
Naringenin can be distributed to various organs, including the brain, liver, kidney, spleen, and heart [30].
β-Glucuronidase–enriched sulfatase primarily hydrolyzes naringenin to glucuronide and sulfate forms [31]. The glucuronide form is predominantly present in the serum. However, in tissues including the brain, heart, liver, and pancreatic tissues, it is present in a sulfated form, indicating glucuronidation and subsequent sulfation within these organs [31].
Various studies have shown that different flavonoids can cross different brain regions to varying extents. One study utilized an established ECV304 cell model for
Peng
Metabolism
To form aglycones, including apigenin, apiferol, eriodictyol, and hesperetin, naringenin undergoes dehydrogenation, hydrogenation, hydroxylation, and methylation. Naringenin and its aglycones are sulfated or glucuronated by phase II metabolic enzymes in the stomach, liver, and other tissues. Thirty-nine flavonoid metabolites are generated by naringenin and its derivatives, including apigenin, apiferol, eriodictyol, and hesperetin, through sulfation or glucuronidation. These metabolites exist as
Moreover, unabsorbed flavonoids produce phenolic catabolites within the gut microbiome. Forty-six phenolic catabolites were identified, including phenylpropenoic acid, phenylpropionic acid, phenylacetic acid, benzoic acid, benzenetriol, and benzoylglycine derivatives [35].
Under anaerobic conditions, when cultured with human fecal solutions, naringenin undergoes metabolism for >24 h to yield HPPA, 3-(phenyl)propionic acid, and minor quantities of 3-(4'-hydroxyphenyl)acetic acid [36]. The NADH-dependent reductase enzyme of the human colonic anaerobe
The degradation of flavanones, including hesperetin-7-
Excretion
Naringenin is excreted via the following two routes: urine and bile. Initially, approximately 1%–30% of the ingested naringenin is excreted in the urine. Differences in urinary excretion may be due to individual differences in liver function and differences in intake according to the naringenin level, which is more abundant in citrus peels [40].
Naringenin glucuronides, especially M2, are observed in bile, whereas naringenin sulfate is not detected. Moreover, the hepatic metabolism of naringenin glucuronide is more efficient than the intestinal metabolism [41]. Naringenin glucuronides are predominantly absorbed in the upper small intestine, with approximately 27% and 18% excreted in the duodenum and jejunum. Moreover, efflux transporters MRP2 and breast cancer resistance protein-1 compensate for each other, enabling the intraintestinal excretion of flavonoid glucuronides, including naringenin [41].
Preclinical Studies of Naringenin
Cancer
Cancer is a significant cause of mortality worldwide, with its incidence anticipated to increase globally, particularly in low and middle-income countries [42]. Incorporating vegetables and fruits into the diet has been suggested as a promising strategy for preventing cancer. A study encompassing 34 varieties of citrus juices examined their effects on the cell lines of the following four cancer types: lung carcinoma, melanoma, leukemia, and gastric carcinoma [43]. When citrus fruit flavonoids were administered to the same cell lines, naringin and naringenin demonstrated antiproliferative effects starting from a 0.04 mM concentration. Notably, naringenin exhibited more vital growth inhibitory properties than naringin [44]. Here, we addressed colorectal, gastric, lung, breast, ovarian, cervical, prostate, bladder, liver, pancreatic, and skin cancers. We reviewed the
Colorectal and gastric cancers. Colorectal cancer occurs in the colon and rectum, ranking as the third leading cause of cancer-related deaths in the United States in 2023 [45]. As dietary habits play an essential role in the pathogenesis of colorectal cancer, dietary chemotherapy has attracted attention for colorectal cancer prevention [46]. A previous study has demonstrated the protective effects of citrus flavonoids against colorectal cancer and reported that naringenin inhibited HT-29 colon cancer cell proliferation [47]. Treatment with 6-C-(E-phenylethenyl)naringenin (6-CEPN) reduced the levels of autophagy-related protein 7 and beclin-1, which are crucial proteins involved in autophagy in colorectal cancer, thereby inducing autophagy and apoptosis by arresting cell proliferation at the G1 phase of the cell cycle [48]. Treatment with naringenin reduced cyclin D1 levels in the HCT116 and SW480 colorectal cancer cell lines (Fig. 2A) [49]. Moreover, recent studies have demonstrated that loading naringenin into nanostructured lipid carriers with a 98-nm particle size enhances its bioavailability and cellular absorption, serving as a potent trigger for cell apoptosis in HT-29 cells [50].
-
Fig. 2. The signaling pathways of naringenin in cancer. (A) Naringenin arrests the cell cycle by inhibiting cyclin D. (B) Naringenin inhibits cell proliferation by inhibiting the JAK/STAT pathway and suppresses cell proliferation, migration and invasion by inhibiting the PI3K/Akt pathway. (C) Naringenin induces apoptosis by regulating pro- and anti-apoptosis factors. (D) Naringenin decreases cell survival by inhibiting ERK1/2, JNK, and p38. (E) Naringenin attenuates metastasis by inhibiting the activity of NF-κB and AP-1. (F) Naringenin decreases cell migration and invasion by inhibiting the activity of Smad-3.
In 2020, the fifth most diagnosed cancer and the fourth leading cause of cancer-related death worldwide was gastric cancer [45, 51]. The causes of gastric cancer include
Lung cancer. Lung cancer is a commonly diagnosed cancer, accounting for approximately 11.6% of all cancer diagnoses [57]. In 2023, approximately 238,340 new cases of lung cancer would be diagnosed in the United States, and nearly 127,070 individuals would be die from the disease [45]. Lung cancer is the primary cause of cancer-related death (accounting for 18.4% of all cancer-related deaths), causing severe economic burden and social difficulties [45, 58]. Smoking is the primary cause of lung cancer, with asbestos exposure, air pollution, chronic polycyclic aromatic hydrocarbon exposure, and genetic predisposition as additional factors [59]. Naringenin oral administration significantly reduced the number of metastatic tumor cells in the lungs and extended the lifespan of tumor-resected mice. Moreover, naringenin increased the proportion of T cells expressing interferon-γ and interleukin-2 and enhanced antitumor activity [60]. In mice with pulmonary fibrosis, a 100 mg/kg naringenin dose decreased the risk of lung metastasis. Naringenin treatment increased the levels of transforming growth factor (TGF)-β1 and CD4+CD25+Foxp3+ regulatory T cells [61].
Breast cancer. In 2020, breast cancer was the most common malignancy among females, accounting for 11.7%of new cancer cases worldwide [51]. In a breast cancer mouse model, naringenin enhanced antitumor activity when administered with doxorubicin and metformin compared with doxorubicin alone [65]. In a mouse model, the co-administration of naringenin with cryptotanshinone reduced JAK2/STAT3 phosphorylation and decreased the CD4+CD25+Foxp3+ T cell population within the tumor (Fig. 2B) [66]. Naringenin decreased TGF-β1 secretion levels in breast cancer cells and inhibited the metastasis of lung tumors [67]. Moreover, the inhibition of 4T1 tumor metastasis increased survival in mice. Naringenin did not affect TGF-β1 transcription; however, it hindered its transport from the trans-Golgi network [67].
In
Ovarian and cervical cancers. In 2020, ovarian cancer accounted for 1.6% of new cancer diagnoses and 2.1% of all cancer-related deaths worldwide [51]. It mainly developed in postmenopausal females and was primarily caused by mutations in the
In 2020, cervical cancer accounted for 3.1% of all cancer diagnoses and comprised 3.4% of all cancer-related deaths worldwide [51]. Infection with oncogenic subtypes of the human papillomavirus was the primary causative factor [73]. Owing to the low naringenin bioavailability, studies were conducted in combination with nanoparticles in human cervical cancer HeLa cells [74]. Naringenin-loaded nanoparticles (NARNPs) exhibited more significant cell toxicity than naringenin alone. NARNPs increased intracellular ROS levels and lipid peroxidation status while reducing glutathione (GSH) levels. Furthermore, NARNPs treatment led to MMP alterations and an increased apoptotic index in cancer cells. These results underscore the potential of NARNPs as a promising strategy for potential anticancer therapy in cervical cancer [74].
Bladder and prostate cancer. In 2020 bladder cancer was the 10th most common cancer worldwide, with an annual incidence of 573,000 cases and 212,536 deaths [51]. It occurs more frequently in males than females, and the incidence increases with age [75]. Naringenin treatment for 24 h reduced cell viability in TSGH8301 bladder cancer cells [76]. Furthermore, by downregulating MMP-2 and Akt activities, naringenin dose-dependently decreased TSGH8301 cell migration [76].
Prostate cancer is the most common type of male urogenital malignancy, and risk factors, including genetic predisposition, race, and age, are previously reported [45, 77]. Naringenin can reverse the expression of proteins involved in the epithelial-mesenchymal transition (EMT) in human prostate cancer cells, specifically PC-3 cells, and inhibit the activity of urokinase plasminogen activator, thereby leading to cell migration suppression [78]. Moreover, naringenin treatment inhibited cell proliferation and reduced cell motility in MAT-LyLu prostate cancer cells. Naringenin inhibited cell migration by reducing
Liver cancer. Hepatocellular carcinoma (HCC) associated with fibrosis and chronic inflammation is influenced by various risk factors, including alcohol consumption, aflatoxin B1, hepatitis B/C virus, infection, and metabolic disorders [81]. In a rat model of liver cancer induced by N-nitroso diethylamine (NDEA), the efficacy of naringenin was evaluated [82]. Following NDEA-induced HCC, naringenin pre- and post-treatment modulated xenobiotic metabolism enzymes, attenuated lipid peroxidation, and reduced liver marker enzyme levels [82].
Naringenin showed potent anticancer effects in diethylnitrosamine-induced HCC cell lines [83]. Additionally, naringenin inhibited the 12-
Pancreatic cancer. Pancreatic cancer is a highly dire and aggressive tumor, being one of the most perilous cancers with a survival rate of only 7% [86, 87]. By suppressing the TGF-β signaling pathway, a central regulator of EMT, naringenin inhibited pancreatic cancer. In addition, it suppressed migration through caspase-3 cleavage, increased ROS levels, and induced cell death via apoptosis signal-regulating kinase (ASK)-1 mediation. First, by inhibiting the TGF-β/Smad-3 signaling pathway, naringenin reduced EMT marker levels (Fig. 2F) [87]. TGF-β is a pivotal regulator of EMT, governing cellular motility, transition, and invasion, and Smad-3 regulates it. Moreover, naringenin augmented the sensitivity of PANC-1 pancreatic cancer cells to gemcitabine, the most potent drug used in pancreatic cancer clinical therapy [87]. Second, the combination treatment of naringenin and hesperetin suppressed migration in PANC-1 pancreatic cells and inhibited FAK and p38 phosphorylation [88]. This study was conducted by treating PANC-1 pancreatic cells with a naringenin and hesperetin combination. The combination of these two compounds targeted caspase-3 cleavage, thereby inhibiting PANC-1 pancreatic cell migration and suppressing FAK and p38 phosphorylation, which was not observed with individual treatments [88]. Lastly, naringenin increased ROS levels in SNU-213 pancreatic cancer cells, thereby triggering ASK-1-mediated cell death [89]. Treating SNU-213 cells with naringenin reduced the expression of p38, JNK, p58, and peroxiredoxin-1, an oxidative stress cell homeostasis regulator.
Skin cancer. Skin cancer, which has several types, is the most commonly diagnosed cancer in the United States. The most common types of skin cancer are non-melanoma skin cancer, basal cell carcinoma, and squamous cell carcinoma; however, they rarely cause death or severe morbidity. Melanoma accounts for approximately 1% of all skin cancers but is the leading cause of skin cancer deaths [90]. In skin cancer, naringenin inhibits glyoxalase-1 activity, increases ROS production, induces apoptosis, and inhibits melanoma metastasis by inhibiting two-pore channel 2 (TPC2). First, naringenin induced apoptosis in A431 human skin cancer cells [91]. In addition, it increased ROS production, induced cell cycle arrest in the G0/G1 phase, and enhanced caspase-3 activity. Second, in a skin papilloma mouse model, the preventive effects of naringenin were evaluated [92]. In both pre- and post-treatment models, naringenin reduced the skin papilloma. Biochemical studies have reported that naringenin decreased glyoxalase-1 activity, indicating that it increases oxidative damage in tumors. Lastly, naringenin inhibited TPC2 and melanoma cell angiogenesis [93]. Naringenin inhibited TPC2 and VEGF angiogenesis activation by interfering with intracellular calcium signaling.
Metabolic Disorders
Metabolism is the highly regulated process of separating consumed food into simple components, including carbohydrates, proteins, and fats [94]. Diabetes, obesity, hyperlipidemia, hypertension, cardiac toxicity, hypertrophy, hyperglycemia, steatosis, hepatic protection, and atherosclerosis are the most common metabolic disorder-related diseases. This chapter will introduce the efficacy of naringenin in treating metabolic disorders.
Diabetes. Diabetes is a severe, non-infectious endocrine metabolic disorder that can lead to complications in multiple organs [95]. Diabetes is characterized by elevated blood glucose levels due to insufficient insulin secretion by pancreatic β cells or increased insulin resistance to glucose [96, 97]. Diabetes can lead to several complications, including renal failure, liver dysfunction, blindness, cardiac arrest, stroke, and neurological damage [94, 98, 99]. Therefore, maintaining normal blood glucose levels as a preventive measure against diabetes is imperative.
In
In
Obesity and hyperlipidemia. Overweight and obesity are characterized by abnormal or excessive fat accumulation that can pose health risks. A body mass index >25 kg/m2 is considered overweight, and >30 kg/m2 is considered obese. In the United States, 40% of the population is considered obese [109, 110]. Hyperlipidemia is characterized by abnormally high levels of lipids and cholesterol in the blood, predisposing the individual to atherosclerosis and other arterial diseases. Hyperlipidemia is diagnosed when the total cholesterol, low-density lipoprotein (LDL)-cholesterol, and TG levels are ≥240, ≥160 mg/dL, ≥150 mg/dL, respectively [111]. Obesity is a major cause of metabolic syndrome, including diabetes, high blood pressure, and hyperlipidemia, ultimately causing atherosclerosis and cardiovascular diseases [112, 113]. The prevalence of obesity worldwide is mainly due to a high-fat-, high-sugar-, westernized diet, highlighting the significance of obesity prevention [114].
In
In
Hypertension. Hypertension is a chronic disease characterized by increased blood pressure and is a significant cause of cardiovascular diseases. Hypertension affects at least 1.4 billion individuals worldwide [123, 124]. Hypertension is a significant risk factor for coronary heart disease, stroke, and chronic kidney disease and leads to premature mortality and morbidity [125]. Therefore, preventing high blood pressure is highly significant.
In
Hyperglycemia. Hyperglycemia is characterized by a fasting blood sugar level of >125 mg/dL and a 2-h postprandial blood sugar level of >180 mg/dL [130-132]. Decreased insulin secretion, reduced glucose utilization, and increased glucose production are the factors contributing to hyperglycemia [132, 133]. The latest data released by the Centers for Disease Control and Prevention revealed that approximately 30.5 and 84 million Americans have diabetes and pre-diabetes, respectively [134].
Naringenin alleviates hyperglycemia by reducing blood sugar levels and protects against inflammation and oxidative stress caused by hyperglycemia. In a Wistar rat model of STZ and nicotinamide-induced diabetes, the hyperglycemia-induced inflammation was alleviated by naringenin [135]. Daily IP treatment with naringenin 50 mg/kg improved hematological indicators, including erythrocyte sedimentation rate, total white blood cell (WBC) count, differential WBC percentage, and platelet count [135]. Moreover, naringenin decreased the level of the pro-inflammatory cytokine, NF-κB [135]. Compared with diabetic rats that did not receive naringenin, those that received naringenin treatment showed decreased fasting blood sugar and glycated hemoglobin levels and increased serum insulin levels [136]. Hyperglycemia was induced by treating Chang cells with glucose, and naringenin treatment increased cell survival and reduced oxidative stress [137]. In an STZ-induced diabetes Sprague-Dawley rat model, naringenin treatment reduced the levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and oxidative stress [137]. When STZ-induced diabetic rats were fed a high-fat diet and subsequently treated with naringenin, hyperglycemia and hyperlipidemia were improved [138]. In addition, treatment with naringenin increased GLUT-4 expression and decreased TNF-α expression [138].
Steatosis and liver disease. Steatosis is characterized by fat accumulation in organs, such as the liver. The normal liver also contains fat but becomes impaired when the fat content exceeds 5% [139]. Nonalcoholic fatty liver disease (NAFLD) is divided into the early stage, nonalcoholic fatty liver (NAFL), and the worsening stage, nonalcoholic steatohepatitis [140]. NAFLD is related to metabolic syndrome, and more than one-third of patients with type 2 diabetes mellitus develop NAFLD [141, 142].
Naringenin inhibits fat accumulation in the liver, thereby alleviating liver diseases, including steatosis and NAFLD. In a mouse model of high-fat diet-induced obesity, naringenin treatment suppressed obesity [143]. Naringenin lowered hepatic TG levels and increased the expression of hepatic fatty acid oxidation and ketogenesis regulators, such as PGC1α [143]. In a mouse model of methionine–choline deficiency diet-induced NAFLD, naringenin suppressed hepatic lipid accumulation and inflammation by inhibiting NLRP3/NF-κB pathway activation [144]. In high-fat diet-induced NAFLD mice, treatment with naringenin activated AMPK inhibited autophagy and lipid accumulation and increased energy expenditure [145]. Furthermore, in high-fat diet-induced NAFLD mice, naringenin suppressed weight gain and reduced TG and total cholesterol levels in the liver and blood [146].
Atherosclerosis. Atherosclerosis is characterized by plaque accumulation in the lining of the arteries and; in severe cases, it can lead to stroke and myocardial infarction [147, 148]. Cholesterol mainly accumulates in the form of LDL [149]. If accumulation continues, blood flow decreases, and hypoxia occurs [149].
By improving blood lipid levels and suppressing plaque accumulation, naringenin suppresses atherosclerosis. Naringenin reduced aortic plaque deposits in a Western diet mouse model [150]. Additionally, naringenin decreased TG and total cholesterol levels [150]. Ldlr−/− mice fed a high-fat-cholesterol diet developed atherosclerosis, and naringenin treatment decreased plaque macrophages and increased smooth muscle cells [151]. By reducing plasma TG and cholesterol levels, naringenin inhibited plaque formation [151]. In ApoE−/− mice with atherosclerosis and vascular aging, naringenin suppressed the excessive production of ROS and increased the activity of antioxidant enzymes in the aorta [152]. Furthermore, the increased SIRT1 activity by naringenin increased the deacetylation and protein expression of the downstream factors, FOXO3a and PGC1α [152]. The administration of naringenin (FA-LNPs/Nrg), an oral nanomedicine made through FA-LNPs encapsulation, to ApoE−/− mice reduced the aortic lesion area and plaque areas [153]. Moreover, FA-LNPs/Nrg treatment reduced blood TG, total cholesterol, and LDL levels and increased HDL levels [153].
Neurodegenerative Diseases
Alzheimer’s disease. AD refers to chronic and persistent memory loss that causes cognitive impairment [154]. AD is characterized by the formation of amyloid plaques and neurofibrillary tangles composed of amyloid-beta (Aβ) and hyperphosphorylated tau [154, 155]. Acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and amyloid precursor protein cleaving enzyme 1 (BACE1) are essential enzymes responsible for AD development [156].
By regulating the PI3K/Akt/GSK-3β pathway and inhibiting AChE activity, naringenin suppresses memory loss. First, in AD-induced
Parkinson’s disease. PD is characterized by the loss of dopaminergic neurons in the midbrain [162]. PD causes motor disorders and may initially cause non-motor disorders, including anosmia, depression, and sleep disorders [163]. The regulation of neuroinflammation, dopamine, and oxidative stress play significant roles in PD [164]. 6-Hydroxydopamine (6-OHDA) is one of the neurotoxins used for inducing PD models by causing damage to dopamine neurons in the nigrostriatum [165]. Paraquat (PQ), a frequently used pesticide, induces oxidative stress and causes PD-like lesions in rodent animal models [166]. Rotenone-induced PD models can reproduce the main pathological features of clinical PD models [167].
Naringenin protects against oxidative damage caused by the PD inducers, including 6-OHDA, PQ, and rotenone. First, in 6-OHDA–induced
Conclusion and Future Prospects
Naringenin is a flavanone and is a well-known polyphenol. Naringenin has various physiological activities and has been shown to positively affect colorectal, gastric, lung, breast, ovarian, cervical, prostate, bladder, liver, pancreatic, and skin cancers. Moreover, naringenin has been shown to positively influence metabolic disorders, including diabetes, obesity, hyperlipidemia, hypertension, hyperglycemia, steatosis, liver disease, and atherosclerosis, as well as neurodegenerative diseases, including AD and PD.
According to clinicaltrials.gov, clinical studies on naringenin and citrus fruit extracts are actively underway. First, clinical studies using extracts have confirmed the safety and pharmacokinetics of naringenin. The serum naringenin concentration was confirmed after the oral administration of citrus extracts. Second, a clinical study using naringenin has been conducted. A study on whether naringenin can prevent hepatitis C virus infection and the effects of naringenin administration on subjective cognitive decline is ongoing. Furthermore, a study has investigated the effects of naringenin combined with β-carotene on energy consumption and glucose metabolism. In this manner, clinical trials on naringenin are actively underway.
These studies have suggested that naringenin can be implemented in clinical trials for the diseases introduced in this review. Overall, naringenin may become a promising preventive and therapeutic option for diseases threatening human health.
Acknowledgments
This work was supported by the National Research Foundation of Korea grant funded by the Korean government (MSIP) (NRF-2021R1C1C1013592).
Author Contributions
S.H.S. supervised the conception of the work. J.H.S. wrote the draft and S.H.S. revised it. All authors approved the final manuscript.
Conflict of Interest
The authors have no financial conflicts of interest to declare.
References
- (WHO). WHO. Cancer. Available online: https://www.who.int/news-room/fact-sheets/detail/cancer. (Accessed on 6 June, 2023).
- Rodriguez-Casado A. 2016. The health potential of fruits and vegetables phytochemicals: notable examples.
Crit. Rev. Food Sci. Nutr. 56 : 1097-1107. - Norat T, Scoccianti C, Boutron-Ruault MC, Anderson A, Berrino F, Cecchini M,
et al . 2015. European code against cancer 4th edition: diet and cancer.Cancer Epidemiol. 39 Suppl 1 : S56-66. - Guarente L. 2006. Sirtuins as potential targets for metabolic syndrome.
Nature 444 : 868-874. - Luo J, Si H, Jia Z, Liu D. 2021. Dietary anti-aging polyphenols and potential mechanisms.
Antioxidants (Basel) 10 : 283. - Santos AL, Lindner AB. 2017. Protein posttranslational modifications: roles in aging and age-related disease.
Oxid. Med. Cell. Longev. 2017 : 5716409. - Reith W. 2018. Neurodegenerative diseases.
Radiologe 58 : 241-258. - Li Z, Zhao T, Shi M, Wei Y, Huang X, Shen J,
et al . 2023. Polyphenols: natural food grade biomolecules for treating neurodegenerative diseases from a multi-target perspective.Front. Nutr. 10 : 1139558. - Patra S, Pradhan B, Nayak R, Behera C, Das S, Patra SK,
et al . 2021. Dietary polyphenols in chemoprevention and synergistic effect in cancer: clinical evidences and molecular mechanisms of action.Phytomedicine 90 : 153554. - Shohag S, Akhter S, Islam S, Sarker T, Sifat MK, Rahman MM,
et al . 2022. Perspectives on the molecular mediators of oxidative stress and antioxidant strategies in the context of neuroprotection and neurolongevity: an extensive review.Oxid. Med. Cell Longev. 2022 : 7743705. - Rivas F, Poblete-Aro C, Pando ME, Allel MJ, Fernandez V, Soto A,
et al . 2022. Effects of polyphenols in aging and neurodegeneration associated with oxidative stress.Curr. Med. Chem. 29 : 1045-1060. - Tufarelli V, Casalino E, D'Alessandro AG, Laudadio V. 2017. Dietary phenolic compounds: biochemistry, metabolism and significance in animal and human health.
Curr. Drug Metab. 18 : 905-913. - Teng H, Chen L. 2019. Polyphenols and bioavailability: an update.
Crit. Rev. Food Sci. Nutr. 59 : 2040-2051. - Di Lorenzo C, Colombo F, Biella S, Stockley C, Restani P. 2021. Polyphenols and human health: the role of bioavailability.
Nutrients 13 : 273. - Barreca D, Gattuso G, Bellocco E, Calderaro A, Trombetta D, Smeriglio A,
et al . 2017. Flavanones: citrus phytochemical with health-promoting properties.Biofactors 43 : 495-506. - Ramesh E, Alshatwi AA. 2013. Naringin induces death receptor and mitochondria-mediated apoptosis in human cervical cancer (SiHa) cells.
Food Chem. Toxicol. 51 : 97-105. - Esaki S, Nishiyama K, Sugiyama N, Nakajima R, Takao Y, Kamiya S. 1994. Preparation and taste of certain glycosides of flavanones and of dihydrochalcones.
Biosci. Biotechnol. Biochem. 58 : 1479-1485. - Shin W, Kim S, Chun KS. 1987. Structure of (R,S)-hesperetin monohydrate.
Acta Crystallogr. Sec. C. 43 : 1946-1949. - Tripoli E, La Guardia M, Giammanco S, Di Majo D, Giammanco M. 2007. Citrus flavonoids: molecular structure, biological activity and nutritional properties: a review.
Food Chem. 104 : 466-479. - Yao LH, Jiang YM, Shi J, TOMÁS-BARBERÁN FA, Datta N, Singanusong R,
et al . 2004. Flavonoids in food and their health benefits.Plant Foods Hum. Nutr. 59 : 113-122. - Graf BA, Milbury PE, Blumberg JB. 2005. Flavonols, flavones, flavanones, and human health: epidemiological evidence.
J. Med. Food 8 : 281-290. - Haytowitz DB, Wu X, Bhagwat S. USDA Database for the Flavonoid Content of Selected Foods, Release 3.3. U.S. Department of Agriculture, Agricultural Research Service, 2018. Nutrient Data Laboratory Home Page: http://www.ars.usda.gov/nutrientdata/flav..
- Ribeiro MH. 2011. Naringinases: occurrence, characteristics, and applications.
Appl. Microbiol. Biotechnol. 90 : 1883-1895. - Yusof S, Ghazali HM, King GS. 1990. Naringin content in local citrus fruits.
Food Chem. 37 : 113-121. - Zhang L, Song L, Zhang P, Liu T, Zhou L, Yang G,
et al . 2015. Solubilities of naringin and naringenin in different solvents and dissociation constants of naringenin.J. Chem. Eng. Data 60 : 932-940. - Justesen U, Knuthsen P, Leth T. 1998. Quantitative analysis of flavonols, flavones, and flavanones in fruits, vegetables and beverages by high-performance liquid chromatography with photo-diode array and mass spectrometric detection.
J. Chromatogr. A. 799 : 101-110. - Nait Chabane M, Al Ahmad A, Peluso J, Muller CD, Ubeaud G. 2009. Quercetin and naringenin transport across human intestinal Caco-2 cells.
J. Pharm. Pharmacol. 61 : 1473-1483. - Xu H, Kulkarni KH, Singh R, Yang Z, Wang SW, Tam VH,
et al . 2009. Disposition of naringenin via glucuronidation pathway is affected by compensating efflux transporters of hydrophilic glucuronides.Mol. Pharm. 6 : 1703-1715. - Kanaze FI, Bounartzi MI, Georgarakis M, Niopas I. 2007. Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects.
Eur. J. Clin. Nutr. 61 : 472-477. - Spencer JPE, Spencer JPE, Crozier A. 2012.
Flavonoids and Related Compounds : Bioavailability and Function , Ed. CRC Press, Hoboken. - Lin SP, Hou YC, Tsai SY, Wang MJ, Chao PD. 2014. Tissue distribution of naringenin conjugated metabolites following repeated dosing of naringin to rats.
Biomed. (Taipei) 4 : 16. - Youdim KA, Qaiser MZ, Begley DJ, Rice-Evans CA, Abbott NJ. 2004. Flavonoid permeability across an in situ model of the bloodbrain barrier.
Free Radic. Biol. Med. 36 : 592-604. - Youdim KA, Dobbie MS, Kuhnle G, Proteggente AR, Abbott NJ, Rice-Evans C. 2003. Interaction between flavonoids and the blood-brain barrier: in vitro studies.
J. Neurochem. 85 : 180-192. - Peng HW, Cheng FC, Huang YT, Chen CF, Tsai TH. 1998. Determination of naringenin and its glucuronide conjugate in rat plasma and brain tissue by high-performance liquid chromatography.
J. Chromatogr. B Biomed. Sci. Appl. 714 : 369-374. - Zeng X, Su W, Zheng Y, He Y, He Y, Rao H,
et al . 2019. Pharmacokinetics, tissue distribution, metabolism, and excretion of naringin in aged rats.Front. Pharmacol. 10 : 34. - Chen T, Wu H, He Y, Pan W, Yan Z, Liao Y,
et al . 2019. Simultaneously quantitative analysis of naringin and its major human gut microbial metabolites naringenin and 3-(4'-Hydroxyphenyl) propanoic acid via stable isotope deuterium-labeling coupled with RRLC-MS/MS method.Molecules 24 : 4287. - Braune A, Gutschow M, Blaut M. 2019. An NADH-dependent reductase from
Eubacterium ramulus catalyzes the stereospecific heteroring cleavage of flavanones and flavanonols.Appl.Environ. Microbiol. 85 : e01233-19. - Jeon SM, Kim HK, Kim HJ, Do GM, Jeong TS, Park YB,
et al . 2007. Hypocholesterolemic and antioxidative effects of naringenin and its two metabolites in high-cholesterol fed rats.Transl. Res. 149 : 15-21. - Pereira-Caro G, Oliver CM, Weerakkody R, Singh T, Conlon M, Borges G,
et al . 2015. Chronic administration of a microencapsulated probiotic enhances the bioavailability of orange juice flavanones in humans.Free Radic. Biol. Med. 84 : 206-214. - Ranka S, Gee JM, Biro L, Brett G, Saha S, Kroon P,
et al . 2008. Development of a food frequency questionnaire for the assessment of quercetin and naringenin intake.Eur. J. Clin. Nutr. 62 : 1131-1138. - Xu HY, Kulkarni KH, Singh R, Yang Z, Wang SWJ, Tam VH,
et al . 2009. Disposition of naringenin via glucuronidation pathway is affected by compensating efflux transporters of hydrophilic glucuronides.Mol. Pharm. 6 : 1703-1715. - Torre LA, Siegel RL, Ward EM, Jemal A. 2016. Global cancer incidence and mortality rates and trends--An update.
Cancer Epidemiol. Biomarkers Prev. 25 : 16-27. - Kawaii S, Tomono Y, Katase E, Ogawa K, Yano M. 1999. Antiproliferative effects of the readily extractable fractions prepared from various citrus juices on several cancer cell lines.
J. Agric.Food Chem. 47 : 2509-2512. - KAWAII S, TOMONO Y, KATASE E, OGAWA K, YANO M. 1999. Antiproliferative activity of flavonoids on several cancer cell lines.
Biosci. Biotechnol. Biochem. 63 : 896-899. - Siegel RL, Miller KD, Wagle NS, Jemal A. 2023. Cancer statistics, 2023.
CA Cancer J. Clin. 73 : 17-48. - Rajamanickam S, Agarwal R. 2008. Natural products and colon cancer: current status and future prospects.
Drug Dev. Res. 69 : 460-471. - Frydoonfar HR, McGrath DR, Spigelman AD. 2003. The variable effect on proliferation of a colon cancer cell line by the citrus fruit flavonoid Naringenin.
Colorectal. Dis. 5 : 149-152. - Zhao Y, Fan D, Ru B, Cheng K-W, Hu S, Zhang J,
et al . 2016. 6-C-(E-phenylethenyl)naringenin induces cell growth inhibition and cytoprotective autophagy in colon cancer cells.Eur. J. Cancer 68 : 38-50. - Song HM, Park GH, Bo HJ, Lee JW, Kim MK, Lee JR,
et al . 2015. Anti-proliferative effect of naringenin through p38-dependent downregulation of cyclin D1 in human colorectal cancer cells.Biomol. Ther. 23 : 339-344. - Raeisi S, Chavoshi H, Mohammadi M, Ghorbani M, Sabzichi M, Ramezani F. 2019. Naringenin-loaded nano-structured lipid carrier fortifies oxaliplatin-dependent apoptosis in HT-29 cell line.
Process Biochem. 83 : 168-175. - Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A,
et al . 2021. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin. 71 : 209-249. - Tan P, Yeoh KG. 2015. Genetics and molecular pathogenesis of gastric adenocarcinoma.
Gastroenterology 149 : 1153-1162 e1153. - Tramacere I, Negri E, Pelucchi C, Bagnardi V, Rota M, Scotti L,
et al . 2012. A meta-analysis on alcohol drinking and gastric cancer risk.Ann. Oncol. 23 : 28-36. - Lordick F, Carneiro F, Cascinu S, Fleitas T, Haustermans K, Piessen G,
et al . 2022. Gastric cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up.Ann. Oncol. 33 : 1005-1020. - Lu L, Mullins CS, Schafmayer C, Zeissig S, Linnebacher M. 2021. A global assessment of recent trends in gastrointestinal cancer and lifestyle-associated risk factors.
Cancer Commun (Lond) 41 : 1137-1151. - Bao L, Liu F, Guo HB, Li Y, Tan BB, Zhang WX,
et al . 2016. Naringenin inhibits proliferation, migration, and invasion as well as induces apoptosis of gastric cancer SGC7901 cell line by downregulation of AKT pathway.Tumor Biol. 37 : 11365-11374. - Lahiri A, Maji A, Potdar PD, Singh N, Parikh P, Bisht B,
et al . 2023. Lung cancer immunotherapy: progress, pitfalls, and promises.Mol. Cancer 22 : 40. - Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. 2018. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
CA Cancer J. Clin. 68 : 394-424. - Kanwal M, Ding XJ, Cao Y. 2017. Familial risk for lung cancer (Review).
Onco. Lett. 13 : 535-542. - Qin L, Jin L, Lu L, Lu X, Zhang C, Zhang F,
et al . 2011. Naringenin reduces lung metastasis in a breast cancer resection model.Protein Cell 2 : 507-516. - Du G, Jin L, Han X, Song Z, Zhang H, Liang W. 2009. Naringenin: a potential immunomodulator for inhibiting lung fibrosis and metastasis.
Cancer Res. 69 : 3205-3212. - Chang HL, Chang YM, Lai SC, Chen KM, Wang KC, Chiu TT,
et al . 2017. Naringenin inhibits migration of lung cancer cells via the inhibition of matrix metalloproteinases-2 and -9.Exp. Ther. Med. 13 : 739-744. - Jin CY, Park C, Hwang HJ, Kim GY, Choi BT, Kim WJ,
et al . 2011. Naringenin up-regulates the expression of death receptor 5 and enhances TRAIL-induced apoptosis in human lung cancer A549 cells.Mol. Nutr. Food Res. 55 : 300-309. - Liu X, Zhao T, Shi Z, Hu C, Li Q, Sun C. 2023. Synergism antiproliferative effects of apigenin and naringenin in NSCLC cells.
Molecules 28 : 4947. - Pateliya B, Burade V, Goswami S. 2021. Combining naringenin and metformin with doxorubicin enhances anticancer activity against triple-negative breast cancer in vitro and in vivo.
Eur. J. Pharmacol. 891 : 173725. - Noori S, Nourbakhsh M, Imani H, Deravi N, Salehi N, Abdolvahabi Z. 2022. Naringenin and cryptotanshinone shift the immune response towards Th1 and modulate T regulatory cells via JAK2/STAT3 pathway in breast cancer.
BMC Complement. Med. Ther. 22 : 145. - Zhang F, Dong W, Zeng W, Zhang L, Zhang C, Qiu Y,
et al . 2016. Naringenin prevents TGF-beta1 secretion from breast cancer and suppresses pulmonary metastasis by inhibiting PKC activation.Breast Cancer Res. 18 : 38. - Wang R, Wang JH, Dong TF, Shen J, Gao XT, Zhou J. 2019. Naringenin has a chemoprotective effect in MDA-MB-231 breast cancer cells via inhibition of caspase-3 and-9 activities.
Oncol. Lett. 17 : 1217-1222. - Harmon AW, Patel YM. 2004. Naringenin inhibits glucose uptake in MCF-7 breast cancer cells: a mechanism for impaired cellular proliferation.
Breast Cancer Res. Treat. 85 : 103-110. - Sun Y, Gu J. 2015. [Study on effect of naringenin in inhibiting migration and invasion of breast cancer cells and its molecular mechanism].
Zhongguo Zhong Yao Za Zhi. 40 : 1144-1150. - Jayson GC, Kohn EC, Kitchener HC, Ledermann JA. 2014. Ovarian cancer.
Lancet 384 : 1376-1388. - Lin C, Zeng Z, Lin Y, Wang P, Cao D, Xie K,
et al . 2022. Naringenin suppresses epithelial ovarian cancer by inhibiting proliferation and modulating gut microbiota.Phytomedicine 106 : 154401. - Cohen PA, Jhingran A, Oaknin A, Denny L. 2019. Cervical cancer.
Lancet 393 : 169-182. - Krishnakumar N, Sulfikkarali N, RajendraPrasad N, Karthikeyan S. 2011. Enhanced anticancer activity of naringenin-loaded nanoparticles in human cervical (HeLa) cancer cells.
Biomed. Prevent. Nutr. 1 : 223-231. - Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M,
et al . 2015. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.Int. J. Cancer 136 : E359-E386. - Liao ACH, Kuo CC, Huang YC, Yeh CW, Hseu YC, Liu JY,
et al . 2014. Naringenin inhibits migration of bladder cancer cells through downregulation of AKT and MMP-2.Mol. Med. Rep. 10 : 1531-1536. - Nguyen-Nielsen M, Borre M. 2016. Diagnostic and therapeutic strategies for prostate cancer.
Semin. Nucl. Med. 46 : 484-490. - Han KY, Chen PN, Hong MC, Hseu YC, Chen KM, Hsu LS,
et al . 2018. Naringenin attenuated prostate cancer invasion via reversal of epithelial-to-mesenchymal transition and inhibited uPA activity.Anticancer Res. 38 : 6753-6758. - Gumushan Aktas H, Akgun T. 2018. Naringenin inhibits prostate cancer metastasis by blocking voltage-gated sodium channels.
Biomed Pharmacother. 106 : 770-775. - Lim W, Park S, Bazer FW, Song G. 2016. Naringenin-induced apoptotic cell death in prostate cancer cells is mediated via the PI3K/AKT and MAPK signaling pathways.
J. Cell. Biochem. 118 : 1118-1131. - Yang YM, Kim SY, Seki E. 2019. Inflammation and liver cancer: molecular mechanisms and therapeutic targets.
Semin. Liver Dis. 39 : 26-42. - Arul D, Subramanian P. 2013. Inhibitory effect of naringenin (citrus flavonone) on N-nitrosodiethylamine induced hepatocarcinogenesis in rats.
Biochem. Biophys. Res. Commun. 434 : 203-209. - Thangavel P, Vaiyapuri M. 2013. Antiproliferative and apoptotic effects of naringin on diethylnitrosamine induced hepatocellular carcinoma in rats.
Biomed. Aging Pathol. 3 : 59-64. - Yen HR, Liu CJ, Yeh CC. 2015. Naringenin suppresses TPA-induced tumor invasion by suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells.
Chem. Biol. Interact. 235 : 1-9. - Kang Q, Gong J, Wang M, Wang Q, Chen F, Cheng K-W. 2019. 6-C-(E-Phenylethenyl)Naringenin attenuates the stemness of hepatocellular carcinoma cells by suppressing Wnt/β-catenin signaling.
J. Agric. Food Chem. 67 : 13939-13947. - Pan P, Huang YW, Oshima K, Yearsley M, Zhang J, Yu J,
et al . 2018. An immunological perspective for preventing cancer with berries.J. Berry Res. 8 : 163-175. - Lou C, Zhang F, Yang M, Zhao J, Zeng W, Fang X,
et al . 2012. Naringenin decreases invasiveness and metastasis by inhibiting TGFbeta-induced epithelial to mesenchymal transition in pancreatic cancer cells.PLoS One 7 : e50956. - Lee J, Kim DH, Kim JH. 2019. Combined administration of naringenin and hesperetin with optimal ratio maximizes the anticancer effect in human pancreatic cancer via down regulation of FAK and p38 signaling pathway.
Phytomedicine 58 : 152762. - Park HJ, Choi YJ, Lee JH, Nam MJ. 2017. Naringenin causes ASK1-induced apoptosis via reactive oxygen species in human pancreatic cancer cells.
Food Chem. Toxicol. 99 : 1-8. - Force USPST, Mangione CM, Barry MJ, Nicholson WK, Chelmow D, Coker TR,
et al . 2023. Screening for skin cancer: US preventive services task force recommendation statement.JAMA 329 : 1290-1295. - Ahamad MS, Siddiqui S, Jafri A, Ahmad S, Afzal M, Arshad M. 2014. Induction of apoptosis and antiproliferative activity of naringenin in human epidermoid carcinoma cell through ROS generation and cell cycle arrest.
PLoS One 9 : e110003. - Kumar R, Bhan Tiku A. 2020. Naringenin suppresses chemically induced skin cancer in two-stage skin carcinogenesis mouse model.
Nutr. Cancer 72 : 976-983. - Pafumi I, Festa M, Papacci F, Lagostena L, Giunta C, Gutla V,
et al . 2017. Naringenin impairs two-pore channel 2 activity and inhibits VEGF-induced angiogenesis.Sci. Rep. 7 : 5121. - Manna P, Das J, Ghosh J, Sil PC. 2010. Contribution of type 1 diabetes to rat liver dysfunction and cellular damage via activation of NOS, PARP, IkappaBalpha/NF-kappaB, MAPKs, and mitochondria-dependent pathways: prophylactic role of arjunolic acid.
Free Radic. Biol. Med. 48 : 1465-1484. - Zhang C, Lu XM, Tan Y, Li B, Miao X, Jin LT,
et al . 2012. Diabetes-induced hepatic pathogenic damage, inflammation, oxidative stress, and insulin resistance was exacerbated in zinc deficient mouse model.PLoS One 7 : e49257. - Gowd V, Nandini CD. 2015. Erythrocytes in the combined milieu of high glucose and high cholesterol shows glycosaminoglycandependent cytoadherence to extracellular matrix components.
Int. J. Biol. Macromol. 73 : 182-188. - Joladarashi D, Salimath PV, Chilkunda ND. 2011. Diabetes results in structural alteration of chondroitin sulfate/dermatan sulfate in the rat kidney: effects on the binding to extracellular matrix components.
Glycobiology 21 : 960-972. - Ritz E. 2006. Diabetic nephropathy.
Saudi J. Kidney Dis. Transpl. 17 : 481-490. - Kam J, Puranik S, Yadav R, Manwaring HR, Pierre S, Srivastava RK,
et al . 2016. Dietary interventions for type 2 diabetes: how millet comes to help.Front. Plant Sci. 7 : 1454. - Ortiz-Andrade RR, Sanchez-Salgado JC, Navarrete-Vazquez G, Webster SP, Binnie M, Garcia-Jimenez S,
et al . 2008. Antidiabetic and toxicological evaluations of naringenin in normoglycaemic and NIDDM rat models and its implications on extra-pancreatic glucose regulation.Diabetes Obes. Metab. 10 : 1097-1104. - Tsai SJ, Huang CS, Mong MC, Kam WY, Huang HY, Yin MC. 2012. Anti-inflammatory and antifibrotic effects of naringenin in diabetic mice.
J. Agric. Food Chem. 60 : 514-521. - Orsolic N, Gajski G, Garaj-Vrhovac V, Dikic D, Prskalo ZS, Sirovina D. 2011. DNA-protective effects of quercetin or naringenin in alloxan-induced diabetic mice.
Eur. J. Pharmacol. 656 : 110-118. - Kannappan S, Anuradha CV. 2010. Naringenin enhances insulin-stimulated tyrosine phosphorylation and improves the cellular actions of insulin in a dietary model of metabolic syndrome.
Eur. J. Nutr. 49 : 101-109. - Priscilla DH, Roy D, Suresh A, Kumar V, Thirumurugan K. 2014. Naringenin inhibits alpha-glucosidase activity: a promising strategy for the regulation of postprandial hyperglycemia in high fat diet fed streptozotocin induced diabetic rats.
Chem. Biol. Interact. 210 : 77-85. - Mutlur Krishnamoorthy R, Carani Venkatraman A. 2017. Polyphenols activate energy sensing network in insulin resistant models.
Chem. Biol. Interact. 275 : 95-107. - Burke AC, Telford DE, Edwards JY, Sutherland BG, Sawyez CG, Huff MW. 2019. Naringenin supplementation to a chow Diet enhances energy expenditure and fatty acid oxidation, and reduces adiposity in lean, pair-fed Ldlr(-/-) mice.
Mol. Nutr. Food Res. 63 : e1800833. - Zygmunt K, Faubert B, MacNeil J, Tsiani E. 2010. Naringenin, a citrus flavonoid, increases muscle cell glucose uptake via AMPK.
Biochem. Biophys. Res. Commun. 398 : 178-183. - Bhattacharya S, Oksbjerg N, Young JF, Jeppesen PB. 2014. Caffeic acid, naringenin and quercetin enhance glucose-stimulated insulin secretion and glucose sensitivity in INS-1E cells.
Diabetes Obes. Metab. 16 : 602-612. - von dem Knesebeck O, Lüdecke D, Luck-Sikorski C, Kim TJ. 2019. Public beliefs about causes of obesity in the USA and in Germany.
Int. J.Public Health 64 : 1139-1146. - Ruhm CJ. 2012. Understanding overeating and obesity.
J. Health Economics 31 : 781-796. - Lu SX, Wu TW, Chou CL, Cheng CF, Wang LY. 2023. Combined effects of hypertension, hyperlipidemia, and diabetes mellitus on the presence and severity of carotid atherosclerosis in community-dwelling elders: a community-based study.
J. Chin. Med. Assoc. 86 : 220-226. - Engin A. 2017. The definition and prevalence of obesity and metabolic syndrome.
Adv. Exp. Med. Biol. 960 : 1-17. - Klop B, Elte JW, Cabezas MC. 2013. Dyslipidemia in obesity: mechanisms and potential targets.
Nutrients 5 : 1218-1240. - Rakhra V, Galappaththy SL, Bulchandani S, Cabandugama PK. 2020. Obesity and the Western diet: how We got here.
Mo Med. 117 : 536-538. - Lee SH, Park YB, Bae KH, Bok SH, Kwon YK, Lee ES,
et al . 1999. Cholesterol-lowering activity of naringenin via inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase and acyl coenzyme A:cholesterol acyltransferase in rats.Ann. Nutr. Metab. 43 : 173-180. - Cho KW, Kim YO, Andrade JE, Burgess JR, Kim YC. 2011. Dietary naringenin increases hepatic peroxisome proliferators-activated receptor alpha protein expression and decreases plasma triglyceride and adiposity in rats.
Eur. J. Nutr. 50 : 81-88. - Zar Kalai F, Han J, Ksouri R, El Omri A, Abdelly C, Isoda H. 2013. Antiobesity effects of an edible halophyte Nitraria retusa forssk in 3T3-L1 preadipocyte differentiation and in C57B6J/L mice fed a high fat diet-induced obesity.
Evid. Based Complement. Alternat. Med. 2013 : 368658. - Yoshida H, Watanabe W, Oomagari H, Tsuruta E, Shida M, Kurokawa M. 2013. Citrus flavonoid naringenin inhibits TLR2 expression in adipocytes.
J. Nutr. Biochem. 24 : 1276-1284. - Cai XY, Wang SX, Wang HL, Liu SW, Liu GS, Chen HB,
et al . 2023. Naringenin inhibits lipid accumulation by activating the AMPK pathway in vivo and in vitro.Food Sci. Hum. Wellness 12 : 1174-1183. - Assini JM, Mulvihill EE, Sutherland BG, Telford DE, Sawyez CG, Felder SL,
et al . 2013. Naringenin prevents cholesterol-induced systemic inflammation, metabolic dysregulation, and atherosclerosis in Ldlr(-)/(-) mice.J. Lipid Res. 54 : 711-724. - Mulvihill EE, Allister EM, Sutherland BG, Telford DE, Sawyez CG, Edwards JY,
et al . 2009. Naringenin prevents dyslipidemia, apolipoprotein B overproduction, and hyperinsulinemia in LDL receptor-null mice with diet-induced insulin resistance.Diabetes 58 : 2198-2210. - Richard AJ, Amini-Vaughan Z, Ribnicky DM, Stephens JM. 2013. Naringenin inhibits adipogenesis and reduces insulin sensitivity and adiponectin expression in adipocytes.
Evid. Based. Complement. Alternat. Med. 2013 : 549750. - Mills KT, Stefanescu A, He J. 2020. The global epidemiology of hypertension.
Nat. Rev. Nephrol. 16 : 223-237. - Mowry FE, Biancardi VC. 2019. Neuroinflammation in hypertension: the renin-angiotensin system versus pro-resolution pathways.
Pharmacol. Res. 144 : 279-291. - Carey RM, Muntner P, Bosworth HB, Whelton PK. 2018. Prevention and control of hypertension: JACC health promotion series.
J. Am. Coll. Cardiol. 72 : 1278-1293. - Liu H, Zhao H, Che J, Yao W. 2022. Naringenin protects against hypertension by regulating lipid disorder and oxidative stress in a rat model.
Kidney Blood Press Res. 47 : 423-432. - Duan B, Li Y, Geng H, Ma A, Yang X. 2021. Naringenin prevents pregnancy-induced hypertension via suppression of JAK/STAT3 signalling pathway in mice.
Int. J. Clin. Pract. 75 : e14509. - Wang Z, Wang S, Zhao J, Yu C, Hu Y, Tu Y,
et al . 2019. Naringenin ameliorates renovascular hypertensive renal damage by normalizing the balance of renin-angiotensin system components in rats.Int. J. Med. Sci. 16 : 644-653. - Ademola Adetokunbo Oyagbemi, Temidayo Olutayo Omobowale, Olumuyiwa Abiola Adejumobi, Abiodun Mary Owolabi, Blessing Seun Ogunpolu, Olufunke Olubunmi Falayi,
et al . 2020. Antihypertensive power of Naringenin is mediated via attenuation of mineralocorticoid receptor (MCR)/angiotensin converting enzyme (ACE)/kidney injury molecule (Kim-1) signaling pathway.Eur. J. Pharmacol. 880 : 173142. - Hammer M, Storey S, Hershey DS, Brady VJ, Davis E, Mandolfo N,
et al . 2019. Hyperglycemia and cancer: a state-of-the-science review.Oncol. Nurs. Forum. 46 : 459-472. - Villegas-Valverde CC, Kokuina E, Breff-Fonseca MC. 2018. Strengthening national health priorities for diabetes prevention and management.
MEDICC Rev. 20 : 5. - Mouri M, Badireddy M. 2023. Hyperglycemia, pp.,
StatPearls , Ed., Treasure Island (FL). - Yari Z, Behrouz V, Zand H, Pourvali K. 2020. New insight into diabetes management: from glycemic index to dietary insulin index.
Curr. Diab. Rev. 16 : 293-300. - Rawlings AM, Sharrett AR, Albert MS, Coresh J, Windham BG, Power MC,
et al . 2019. The association of late-life diabetes status and hyperglycemia with incident mild cognitive impairment and dementia: the ARIC study.Diab. Care 42 : 1248-1254. - Annadurai T, Thomas PA, Geraldine P. 2013. Ameliorative effect of naringenin on hyperglycemia-mediated inflammation in hepatic and pancreatic tissues of Wistar rats with streptozotocin- nicotinamide-induced experimental diabetes mellitus.
Free Radic. Res. 47 : 793-803. - Annadurai T, Muralidharan AR, Joseph T, Hsu MJ, Thomas PA, Geraldine P. 2012. Antihyperglycemic and antioxidant effects of a flavanone, naringenin, in streptozotocin-nicotinamide-induced experimental diabetic rats.
J. Physiol. Biochem. 68 : 307-318. - Kometsi L, Govender K, Mofo Mato EP, Hurchund R, Owira PMO. 2020. By reducing oxidative stress, naringenin mitigates hyperglycaemia-induced upregulation of hepatic nuclear factor erythroid 2-related factor 2 protein.
J. Pharm. Pharmacol. 72 : 1394-1404. - Priscilla DH, Jayakumar M, Thirumurugan K. 2015. Flavanone naringenin: an effective antihyperglycemic and antihyperlipidemic nutraceutical agent on high fat diet fed streptozotocin induced type 2 diabetic rats.
J. Funct. Foods 14 : 363-373. - Bortz JH. 2023. Metabolic-associated fatty liver disease: opportunistic screening at CT colonography.
CT Colonography for Radiographers . pp. 277-290. - Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, Abdelmalek MF, Caldwell S, Barb D,
et al . 2023. AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease.Hepatology 77 : 1797-1835. - Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M,
et al . 2018. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.Nat. Rev. Gastroenterol. Hepatol. 15 : 11-20. - Adams LA, Harmsen S, St Sauver JL, Charatcharoenwitthaya P, Enders FB, Therneau T,
et al . 2010. Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: a community-based cohort study.Am. J. Gastroenterol. 105 : 1567-1573. - Assini JM, Mulvihill EE, Burke AC, Sutherland BG, Telford DE, Chhoker SS,
et al . 2015. Naringenin prevents obesity, hepatic steatosis, and glucose intolerance in male mice independent of fibroblast growth factor 21.Endocrinology 156 : 2087-2102. - Wang Q, Ou Y, Hu G, Wen C, Yue S, Chen C,
et al . 2020. Naringenin attenuates non-alcoholic fatty liver disease by down-regulating the NLRP3/NF-kappaB pathway in mice.Br. J. Pharmacol. 177 : 1806-1821. - Yang Y, Wu Y, Zou J, Wang YH, Xu MX, Huang W,
et al . 2021. Naringenin attenuates non-alcoholic fatty liver disease by enhancing energy expenditure and regulating Autophagy via AMPK.Front. Pharmacol. 12 : 687095. - Yu RY, Gu YP, Zheng LY, Liu ZJ, Bian YF. 2023. Naringenin prevents NAFLD in the diet-induced C57BL/6J obesity model by regulating the intestinal barrier function and microbiota.
J. Funct. Foods 105 : 105578. - Kruk ME, Gage AD, Joseph NT, Danaei G, García-Saisó S, Salomon JA. 2018. Mortality due to low-quality health systems in the universal health coverage era: a systematic analysis of amenable deaths in 137 countries.
Lancet 392 : 2203-2212. - Blagov AV, Markin AM, Bogatyreva AI, Tolstik TV, Sukhorukov VN, Orekhov AN. 2023. The role of macrophages in the pathogenesis of atherosclerosis.
Cells 12 : 522. - Wolf D, Ley K. 2019. Immunity and inflammation in atherosclerosis.
Circ. Res. 124 : 315-327. - Mulvihill EE, Assini JM, Sutherland BG, DiMattia AS, Khami M, Koppes JB,
et al . 2010. Naringenin decreases progression of atherosclerosis by improving dyslipidemia in high-fat-fed low-density lipoprotein receptor-null mice.Arterioscler. Thromb. Vasc. Biol. 30 : 742-U224. - Burke AC, Sutherland BG, Telford DE, Morrow MR, Sawyez CG, Edwards JY,
et al . 2019. Naringenin enhances the regression of atherosclerosis induced by a chow diet in Ldlr(-/-) mice.Atherosclerosis 286 : 60-70. - Wang J, Wu R, Hua Y, Ling S, Xu X. 2023. Naringenin ameliorates vascular senescence and atherosclerosis involving SIRT1 activation.
J. Pharm. Pharmacol. 75 : 1021-1033. - Guo MR, He ZS, Jin ZH, Huang LJ, Yuan JM, Qin SG,
et al . 2023. Oral nanoparticles containing naringenin suppress atherosclerotic progression by targeting delivery to plaque macrophages.Nano Res. 16 : 925-937. - Graham WV, Bonito-Oliva A, Sakmar TP. 2017. Update on Alzheimer's disease therapy and prevention strategies.
Annu. Rev. Med. 68 : 413-430. - Rajmohan R, Reddy PH. 2017. Amyloid-beta and phosphorylated Tau accumulations cause abnormalities at synapses of Alzheimer's disease neurons.
J. Alzheimers Dis. 57 : 975-999. - Tamagno E, Bardini P, Obbili A, Vitali A, Borghi R, Zaccheo D,
et al . 2002. Oxidative stress increases expression and activity of BACE in NT2 neurons.Neurobiol. Dis. 10 : 279-288. - Yang W, Ma J, Liu Z, Lu Y, Hu B, Yu H. 2014. Effect of naringenin on brain insulin signaling and cognitive functions in ICV-STZ induced dementia model of rats.
Neurol. Sci. 35 : 741-751. - Zhang N, Hu ZH, Zhang ZB, Liu GL, Wang YQ, Ren YD,
et al . 2018. Protective role of Naringenin against Aβ -caused damage via ER and PI3K/Akt-mediated pathways.Cell. Mol. Neurobiol. 38 : 549-557. - Heo HJ, Kim MJ, Lee JM, Choi SJ, Cho HY, Hong B,
et al . 2004. Naringenin from citrus junos has an inhibitory effect on acetylcholinesterase and a mitigating effect on amnesia.Dement. Geriatr. Cogn. Disord. 17 : 151-157. - Lee S, Youn K, Lim G, Lee J, Jun M. 2018. In silico docking and in vitro approaches towards BACE1 and cholinesterases inhibitory effect of citrus flavanones.
Molecules 23 : 1509. - Ghofrani S, Joghataei MT, Mohseni S, Baluchnejadmojarad T, Bagheri M, Khamse S,
et al . 2015. Naringenin improves learning and memory in an Alzheimer's disease rat model: insights into the underlying mechanisms.Eur. J. Pharmacol. 764 : 195-201. - Zella MAS, Metzdorf J, Ostendorf F, Maass F, Muhlack S, Gold R,
et al . 2019. Novel immunotherapeutic approaches to target alphasynuclein and related neuroinflammation in Parkinson's disease.Cells 8 : 105. - Sung VW, Nicholas AP. 2013. Nonmotor symptoms in Parkinson's disease: expanding the view of Parkinson's disease beyond a pure motor, pure dopaminergic problem.
Neurol. Clin. 31 : S1-16. - Jayaraj RL, Beiram R, Azimullah S, Meeran MFN, Ojha SK, Adem A,
et al . 2019. Lycopodium attenuates loss of dopaminergic neurons by suppressing oxidative stress and neuroinflammation in a rat model of Parkinson's disease.Molecules 24 : 2182. - Simola N, Morelli M, Carta AR. 2007. The 6-hydroxydopamine model of Parkinson's disease.
Neurotox Res. 11 : 151-167. - Berry C, La Vecchia C, Nicotera P. 2010. Paraquat and Parkinson's disease.
Cell Death Differ. 17 : 1115-1125. - Cannon JR, Tapias V, Na HM, Honick AS, Drolet RE, Greenamyre JT. 2009. A highly reproducible rotenone model of Parkinson's disease.
Neurobiol. Dis. 34 : 279-290. - Lou H, Jing X, Wei X, Shi H, Ren D, Zhang X. 2014. Naringenin protects against 6-OHDA-induced neurotoxicity via activation of the Nrf2/ARE signaling pathway.
Neuropharmacology 79 : 380-388. - Zbarsky V, Datla KP, Parkar S, Rai DK, Aruoma OI, Dexter DT. 2005. Neuroprotective properties of the natural phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson's disease.
Free Radic. Res. 39 : 1119-1125. - Ahmad MH, Fatima M, Ali M, Rizvi MA, Mondal AC. 2021. Naringenin alleviates paraquat-induced dopaminergic neuronal loss in SH-SY5Y cells and a rat model of Parkinson's disease.
Neuropharmacology 201 : 108831. - Dashputre NL, Laddha UD, Pagare TD, Kadam JD, Patil SB, Tajanpure AB,
et al . 2023. Fabrication of nanoparticulate system for oral delivery of Naringenin against paraquat-induced Parkinson's disorder in Wistar rats.Eur. J. Med. Chem. Rep. 8 : 100105. - Madiha S, Batool Z, Shahzad S, Tabassum S, Liaquat L, Afzal A,
et al . 2023. Naringenin, a functional food component, improves motor and non-motor symptoms in animal model of parkinsonism induced by rotenone.Plant Foods Hum. Nutr. 78 : 654-661. - Sonia Angeline M, Sarkar A, Anand K, Ambasta RK, Kumar P. 2013. Sesamol and naringenin reverse the effect of rotenone-induced PD rat model.
Neuroscience 254 : 379-394.
Related articles in JMB

Article
Review
J. Microbiol. Biotechnol. 2024; 34(12): 2425-2438
Published online December 28, 2024 https://doi.org/10.4014/jmb.2410.10006
Copyright © The Korean Society for Microbiology and Biotechnology.
A Comprehensive Review of Naringenin, a Promising Phytochemical with Therapeutic Potential
Jun Hong Shin1 and Seung Ho Shin1,2*
1Department of Food and Nutrition, Gyeongsang National University, Jinju 52828, Republic of Korea
2Department of Bio & Medical Bigdata (BK4 Program), Gyeongsang National University, Jinju 52828, Republic of Korea
Correspondence to:Seung Ho Shin, shshin@gnu.ac.kr
Abstract
Disorders, including cancer, metabolic disorders, and neurodegenerative diseases, can threaten human health; therefore, disease prevention is essential. Naringenin, a phytochemical with low toxicity, has been used in various disease prevention studies. This study aimed to comprehensively review the effects of naringenin on human health. First, we introduced the general characteristics of naringenin and its pharmacokinetic features when absorbed in the body. Next, we summarized the inhibitory effects of naringenin on colorectal, gastric, lung, breast, ovarian, cervical, prostate, bladder, liver, pancreatic, and skin cancers in preclinical studies. Lastly, we investigated the inhibitory effects of naringenin on metabolic disorders, including diabetes, obesity, hyperlipidemia, hypertension, cardiac toxicity, hypertrophy, steatosis, liver disease, and arteriosclerosis, as well as on neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. In conclusion, naringenin may serve as a significant natural compound that benefits human health.
Keywords: Phytochemical, naringenin, cancer, metabolic disorder, neurodegenerative disease
Introduction
Advances in medical technology have increased human life expectancy; however, aging and westernized eating habits have led to the development of various diseases, including cancer, metabolic disorders, and neurodegenerative diseases. Cancer is one of the leading causes of death in humans, and its prevalence is expected to continue to increase, according to the World Health Organization (WHO) [1]. Cancer is treated by a combination of treatments, including surgery and chemotherapy; however, owing to the side effects, prevention through healthy eating is more essential [2, 3]. Furthermore, healthy eating habits are crucial in alleviating metabolic disorders, including obesity. Metabolic disorders can significantly lead to cardiovascular diseases and subsequent death [4]. Increased reactive oxygen species (ROS) due to aging can induce neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD) [5-7]. Prevention of neurodegenerative diseases is essential because the cure is impossible, and the cause remains unclear [8].
Polyphenols, which can be used as a solution for suppressing the onset of diseases, are naturally derived compounds with low toxicity and beneficial effects [9-11]. Polyphenols are abundant in vegetables and fruits and have antioxidant activity, showing beneficial effects in various diseases [12, 13]. Polyphenols include flavonoids and non-flavonoids [14]. Naringenin, a member of the flavonoid family, is a flavanone mainly noted in citrus fruits [15]. Naringenin has antioxidant, anti-inflammatory, and anti-viral effects and lowers the risk of cardiovascular disease, metabolic syndrome, and cancer [16].
We here comprehensively review the various effects of naringenin. First, we describe the sources of naringenin and its characteristics. Second, we discuss the pharmacokinetic aspects of naringenin and explain how it is absorbed, distributed, metabolized, and extracted in the body. Third, we discuss the effects of naringenin on cancer, metabolic disorders, and neurodegenerative diseases. Additionally, we summarize the inhibitory effects of naringenin on colorectal, gastric, lung, breast, ovarian, cervical, prostate, bladder, liver, pancreatic, and skin cancers. Diabetes, obesity, hyperlipidemia, hypertension, cardiac toxicity, hypertrophy, steatosis, liver disease, and arteriosclerosis are described in the metabolic disorder section. Finally, we here discuss the effects of naringenin on neurodegenerative diseases, including AD and PD.
Natural Sources of Naringenin
Naringenin ((2S)-5,7-dihydroxy-2-(4-hydroxyphenyl)-2,3-dihydrochromen-4-one) is a flavanone, a type of flavonoid, and is colorless and odorless (Fig. 1) [17, 18]. With a molecular weight of 272.256 g/mol and a melting point of 251°C, naringenin demonstrates favorable solubility in organic solvents, including ethanol, dimethylformamide, and dimethyl sulfoxide. Conversely, its solubility in buffered aqueous solutions is limited, reaching approximately 475 mg/l [19-21].
-
Figure 1. The structure and natural sources of naringenin.
Naringenin is the most abundant in grapefruit, with a content of 53.00 mg/100 g. The contents of naringenin in other fruits are as follows: yuzu, 24.82mg/100g; pummelo, 24.72mg/100 g; orange, 15.32 mg/100 g; tangerine, 10.02 mg/100 g; and lime, 3.40 mg/100 g (Fig. 1) [22].
Moreover, in humans, the naringenin content is crucial owing to its conversion into naringenin by naringinase. This breakdown process occurs in two steps. First, naringinase exhibits α-L-rhamnosidase activity, thereby leading to naringin hydrolysis into rhamnose and prunin. Second, prunin is further hydrolyzed by the β-D-glucosidase activity of naringinase, subsequently forming naringenin and glucose [23].
Citrus fruits, such as musk lime, Mexican lime, rough lime, pummelo, and mandarin orange, are abundant in naringin, similar to naringenin. Pummelós peel (3,910 μg/g) contains more naringin content than its juice (220 μg/g). Similarly, the peel, juice, and seeds of rough lime have naringin contents of 517, 98, and 29 μg/g, respectively [24].
Pharmacokinetics of Naringenin
Absorption
Naringenin is absorbed in the duodenum, jejunum, ileum, cecum, and colon; however, its systemic absorption rate is limited [25, 26].
Studies conducted in human intestinal Caco-2 cells [27] have reported that naringenin is partially absorbed through passive diffusion, and pH changes do not affect its absorption. Furthermore, it has been identified as a substrate for adenosine triphosphate (ATP)-dependent transport facilitated by multidrug resistance-associated protein 1. Another study using a murine intestinal tract model [28] has shown that the highest absorption rate (68%) of naringenin occurred in the colon. The following were the absorption rates in different parts of the intestine: duodenum 47%; terminal ileum 42%; and jejunum 39%. Moreover, a pharmacokinetic study in humans [29] has noted the following parameters related to a 135-mg naringenin oral dose: area under the plasma concentration-time curve (AUC0-∞) of 9,424.52 ng h/mL; elimination half-life, 2.31 h; and relative cumulative urinary excretion, 5.81%.
Distribution
Naringenin can be distributed to various organs, including the brain, liver, kidney, spleen, and heart [30].
β-Glucuronidase–enriched sulfatase primarily hydrolyzes naringenin to glucuronide and sulfate forms [31]. The glucuronide form is predominantly present in the serum. However, in tissues including the brain, heart, liver, and pancreatic tissues, it is present in a sulfated form, indicating glucuronidation and subsequent sulfation within these organs [31].
Various studies have shown that different flavonoids can cross different brain regions to varying extents. One study utilized an established ECV304 cell model for
Peng
Metabolism
To form aglycones, including apigenin, apiferol, eriodictyol, and hesperetin, naringenin undergoes dehydrogenation, hydrogenation, hydroxylation, and methylation. Naringenin and its aglycones are sulfated or glucuronated by phase II metabolic enzymes in the stomach, liver, and other tissues. Thirty-nine flavonoid metabolites are generated by naringenin and its derivatives, including apigenin, apiferol, eriodictyol, and hesperetin, through sulfation or glucuronidation. These metabolites exist as
Moreover, unabsorbed flavonoids produce phenolic catabolites within the gut microbiome. Forty-six phenolic catabolites were identified, including phenylpropenoic acid, phenylpropionic acid, phenylacetic acid, benzoic acid, benzenetriol, and benzoylglycine derivatives [35].
Under anaerobic conditions, when cultured with human fecal solutions, naringenin undergoes metabolism for >24 h to yield HPPA, 3-(phenyl)propionic acid, and minor quantities of 3-(4'-hydroxyphenyl)acetic acid [36]. The NADH-dependent reductase enzyme of the human colonic anaerobe
The degradation of flavanones, including hesperetin-7-
Excretion
Naringenin is excreted via the following two routes: urine and bile. Initially, approximately 1%–30% of the ingested naringenin is excreted in the urine. Differences in urinary excretion may be due to individual differences in liver function and differences in intake according to the naringenin level, which is more abundant in citrus peels [40].
Naringenin glucuronides, especially M2, are observed in bile, whereas naringenin sulfate is not detected. Moreover, the hepatic metabolism of naringenin glucuronide is more efficient than the intestinal metabolism [41]. Naringenin glucuronides are predominantly absorbed in the upper small intestine, with approximately 27% and 18% excreted in the duodenum and jejunum. Moreover, efflux transporters MRP2 and breast cancer resistance protein-1 compensate for each other, enabling the intraintestinal excretion of flavonoid glucuronides, including naringenin [41].
Preclinical Studies of Naringenin
Cancer
Cancer is a significant cause of mortality worldwide, with its incidence anticipated to increase globally, particularly in low and middle-income countries [42]. Incorporating vegetables and fruits into the diet has been suggested as a promising strategy for preventing cancer. A study encompassing 34 varieties of citrus juices examined their effects on the cell lines of the following four cancer types: lung carcinoma, melanoma, leukemia, and gastric carcinoma [43]. When citrus fruit flavonoids were administered to the same cell lines, naringin and naringenin demonstrated antiproliferative effects starting from a 0.04 mM concentration. Notably, naringenin exhibited more vital growth inhibitory properties than naringin [44]. Here, we addressed colorectal, gastric, lung, breast, ovarian, cervical, prostate, bladder, liver, pancreatic, and skin cancers. We reviewed the
Colorectal and gastric cancers. Colorectal cancer occurs in the colon and rectum, ranking as the third leading cause of cancer-related deaths in the United States in 2023 [45]. As dietary habits play an essential role in the pathogenesis of colorectal cancer, dietary chemotherapy has attracted attention for colorectal cancer prevention [46]. A previous study has demonstrated the protective effects of citrus flavonoids against colorectal cancer and reported that naringenin inhibited HT-29 colon cancer cell proliferation [47]. Treatment with 6-C-(E-phenylethenyl)naringenin (6-CEPN) reduced the levels of autophagy-related protein 7 and beclin-1, which are crucial proteins involved in autophagy in colorectal cancer, thereby inducing autophagy and apoptosis by arresting cell proliferation at the G1 phase of the cell cycle [48]. Treatment with naringenin reduced cyclin D1 levels in the HCT116 and SW480 colorectal cancer cell lines (Fig. 2A) [49]. Moreover, recent studies have demonstrated that loading naringenin into nanostructured lipid carriers with a 98-nm particle size enhances its bioavailability and cellular absorption, serving as a potent trigger for cell apoptosis in HT-29 cells [50].
-
Figure 2. The signaling pathways of naringenin in cancer. (A) Naringenin arrests the cell cycle by inhibiting cyclin D. (B) Naringenin inhibits cell proliferation by inhibiting the JAK/STAT pathway and suppresses cell proliferation, migration and invasion by inhibiting the PI3K/Akt pathway. (C) Naringenin induces apoptosis by regulating pro- and anti-apoptosis factors. (D) Naringenin decreases cell survival by inhibiting ERK1/2, JNK, and p38. (E) Naringenin attenuates metastasis by inhibiting the activity of NF-κB and AP-1. (F) Naringenin decreases cell migration and invasion by inhibiting the activity of Smad-3.
In 2020, the fifth most diagnosed cancer and the fourth leading cause of cancer-related death worldwide was gastric cancer [45, 51]. The causes of gastric cancer include
Lung cancer. Lung cancer is a commonly diagnosed cancer, accounting for approximately 11.6% of all cancer diagnoses [57]. In 2023, approximately 238,340 new cases of lung cancer would be diagnosed in the United States, and nearly 127,070 individuals would be die from the disease [45]. Lung cancer is the primary cause of cancer-related death (accounting for 18.4% of all cancer-related deaths), causing severe economic burden and social difficulties [45, 58]. Smoking is the primary cause of lung cancer, with asbestos exposure, air pollution, chronic polycyclic aromatic hydrocarbon exposure, and genetic predisposition as additional factors [59]. Naringenin oral administration significantly reduced the number of metastatic tumor cells in the lungs and extended the lifespan of tumor-resected mice. Moreover, naringenin increased the proportion of T cells expressing interferon-γ and interleukin-2 and enhanced antitumor activity [60]. In mice with pulmonary fibrosis, a 100 mg/kg naringenin dose decreased the risk of lung metastasis. Naringenin treatment increased the levels of transforming growth factor (TGF)-β1 and CD4+CD25+Foxp3+ regulatory T cells [61].
Breast cancer. In 2020, breast cancer was the most common malignancy among females, accounting for 11.7%of new cancer cases worldwide [51]. In a breast cancer mouse model, naringenin enhanced antitumor activity when administered with doxorubicin and metformin compared with doxorubicin alone [65]. In a mouse model, the co-administration of naringenin with cryptotanshinone reduced JAK2/STAT3 phosphorylation and decreased the CD4+CD25+Foxp3+ T cell population within the tumor (Fig. 2B) [66]. Naringenin decreased TGF-β1 secretion levels in breast cancer cells and inhibited the metastasis of lung tumors [67]. Moreover, the inhibition of 4T1 tumor metastasis increased survival in mice. Naringenin did not affect TGF-β1 transcription; however, it hindered its transport from the trans-Golgi network [67].
In
Ovarian and cervical cancers. In 2020, ovarian cancer accounted for 1.6% of new cancer diagnoses and 2.1% of all cancer-related deaths worldwide [51]. It mainly developed in postmenopausal females and was primarily caused by mutations in the
In 2020, cervical cancer accounted for 3.1% of all cancer diagnoses and comprised 3.4% of all cancer-related deaths worldwide [51]. Infection with oncogenic subtypes of the human papillomavirus was the primary causative factor [73]. Owing to the low naringenin bioavailability, studies were conducted in combination with nanoparticles in human cervical cancer HeLa cells [74]. Naringenin-loaded nanoparticles (NARNPs) exhibited more significant cell toxicity than naringenin alone. NARNPs increased intracellular ROS levels and lipid peroxidation status while reducing glutathione (GSH) levels. Furthermore, NARNPs treatment led to MMP alterations and an increased apoptotic index in cancer cells. These results underscore the potential of NARNPs as a promising strategy for potential anticancer therapy in cervical cancer [74].
Bladder and prostate cancer. In 2020 bladder cancer was the 10th most common cancer worldwide, with an annual incidence of 573,000 cases and 212,536 deaths [51]. It occurs more frequently in males than females, and the incidence increases with age [75]. Naringenin treatment for 24 h reduced cell viability in TSGH8301 bladder cancer cells [76]. Furthermore, by downregulating MMP-2 and Akt activities, naringenin dose-dependently decreased TSGH8301 cell migration [76].
Prostate cancer is the most common type of male urogenital malignancy, and risk factors, including genetic predisposition, race, and age, are previously reported [45, 77]. Naringenin can reverse the expression of proteins involved in the epithelial-mesenchymal transition (EMT) in human prostate cancer cells, specifically PC-3 cells, and inhibit the activity of urokinase plasminogen activator, thereby leading to cell migration suppression [78]. Moreover, naringenin treatment inhibited cell proliferation and reduced cell motility in MAT-LyLu prostate cancer cells. Naringenin inhibited cell migration by reducing
Liver cancer. Hepatocellular carcinoma (HCC) associated with fibrosis and chronic inflammation is influenced by various risk factors, including alcohol consumption, aflatoxin B1, hepatitis B/C virus, infection, and metabolic disorders [81]. In a rat model of liver cancer induced by N-nitroso diethylamine (NDEA), the efficacy of naringenin was evaluated [82]. Following NDEA-induced HCC, naringenin pre- and post-treatment modulated xenobiotic metabolism enzymes, attenuated lipid peroxidation, and reduced liver marker enzyme levels [82].
Naringenin showed potent anticancer effects in diethylnitrosamine-induced HCC cell lines [83]. Additionally, naringenin inhibited the 12-
Pancreatic cancer. Pancreatic cancer is a highly dire and aggressive tumor, being one of the most perilous cancers with a survival rate of only 7% [86, 87]. By suppressing the TGF-β signaling pathway, a central regulator of EMT, naringenin inhibited pancreatic cancer. In addition, it suppressed migration through caspase-3 cleavage, increased ROS levels, and induced cell death via apoptosis signal-regulating kinase (ASK)-1 mediation. First, by inhibiting the TGF-β/Smad-3 signaling pathway, naringenin reduced EMT marker levels (Fig. 2F) [87]. TGF-β is a pivotal regulator of EMT, governing cellular motility, transition, and invasion, and Smad-3 regulates it. Moreover, naringenin augmented the sensitivity of PANC-1 pancreatic cancer cells to gemcitabine, the most potent drug used in pancreatic cancer clinical therapy [87]. Second, the combination treatment of naringenin and hesperetin suppressed migration in PANC-1 pancreatic cells and inhibited FAK and p38 phosphorylation [88]. This study was conducted by treating PANC-1 pancreatic cells with a naringenin and hesperetin combination. The combination of these two compounds targeted caspase-3 cleavage, thereby inhibiting PANC-1 pancreatic cell migration and suppressing FAK and p38 phosphorylation, which was not observed with individual treatments [88]. Lastly, naringenin increased ROS levels in SNU-213 pancreatic cancer cells, thereby triggering ASK-1-mediated cell death [89]. Treating SNU-213 cells with naringenin reduced the expression of p38, JNK, p58, and peroxiredoxin-1, an oxidative stress cell homeostasis regulator.
Skin cancer. Skin cancer, which has several types, is the most commonly diagnosed cancer in the United States. The most common types of skin cancer are non-melanoma skin cancer, basal cell carcinoma, and squamous cell carcinoma; however, they rarely cause death or severe morbidity. Melanoma accounts for approximately 1% of all skin cancers but is the leading cause of skin cancer deaths [90]. In skin cancer, naringenin inhibits glyoxalase-1 activity, increases ROS production, induces apoptosis, and inhibits melanoma metastasis by inhibiting two-pore channel 2 (TPC2). First, naringenin induced apoptosis in A431 human skin cancer cells [91]. In addition, it increased ROS production, induced cell cycle arrest in the G0/G1 phase, and enhanced caspase-3 activity. Second, in a skin papilloma mouse model, the preventive effects of naringenin were evaluated [92]. In both pre- and post-treatment models, naringenin reduced the skin papilloma. Biochemical studies have reported that naringenin decreased glyoxalase-1 activity, indicating that it increases oxidative damage in tumors. Lastly, naringenin inhibited TPC2 and melanoma cell angiogenesis [93]. Naringenin inhibited TPC2 and VEGF angiogenesis activation by interfering with intracellular calcium signaling.
Metabolic Disorders
Metabolism is the highly regulated process of separating consumed food into simple components, including carbohydrates, proteins, and fats [94]. Diabetes, obesity, hyperlipidemia, hypertension, cardiac toxicity, hypertrophy, hyperglycemia, steatosis, hepatic protection, and atherosclerosis are the most common metabolic disorder-related diseases. This chapter will introduce the efficacy of naringenin in treating metabolic disorders.
Diabetes. Diabetes is a severe, non-infectious endocrine metabolic disorder that can lead to complications in multiple organs [95]. Diabetes is characterized by elevated blood glucose levels due to insufficient insulin secretion by pancreatic β cells or increased insulin resistance to glucose [96, 97]. Diabetes can lead to several complications, including renal failure, liver dysfunction, blindness, cardiac arrest, stroke, and neurological damage [94, 98, 99]. Therefore, maintaining normal blood glucose levels as a preventive measure against diabetes is imperative.
In
In
Obesity and hyperlipidemia. Overweight and obesity are characterized by abnormal or excessive fat accumulation that can pose health risks. A body mass index >25 kg/m2 is considered overweight, and >30 kg/m2 is considered obese. In the United States, 40% of the population is considered obese [109, 110]. Hyperlipidemia is characterized by abnormally high levels of lipids and cholesterol in the blood, predisposing the individual to atherosclerosis and other arterial diseases. Hyperlipidemia is diagnosed when the total cholesterol, low-density lipoprotein (LDL)-cholesterol, and TG levels are ≥240, ≥160 mg/dL, ≥150 mg/dL, respectively [111]. Obesity is a major cause of metabolic syndrome, including diabetes, high blood pressure, and hyperlipidemia, ultimately causing atherosclerosis and cardiovascular diseases [112, 113]. The prevalence of obesity worldwide is mainly due to a high-fat-, high-sugar-, westernized diet, highlighting the significance of obesity prevention [114].
In
In
Hypertension. Hypertension is a chronic disease characterized by increased blood pressure and is a significant cause of cardiovascular diseases. Hypertension affects at least 1.4 billion individuals worldwide [123, 124]. Hypertension is a significant risk factor for coronary heart disease, stroke, and chronic kidney disease and leads to premature mortality and morbidity [125]. Therefore, preventing high blood pressure is highly significant.
In
Hyperglycemia. Hyperglycemia is characterized by a fasting blood sugar level of >125 mg/dL and a 2-h postprandial blood sugar level of >180 mg/dL [130-132]. Decreased insulin secretion, reduced glucose utilization, and increased glucose production are the factors contributing to hyperglycemia [132, 133]. The latest data released by the Centers for Disease Control and Prevention revealed that approximately 30.5 and 84 million Americans have diabetes and pre-diabetes, respectively [134].
Naringenin alleviates hyperglycemia by reducing blood sugar levels and protects against inflammation and oxidative stress caused by hyperglycemia. In a Wistar rat model of STZ and nicotinamide-induced diabetes, the hyperglycemia-induced inflammation was alleviated by naringenin [135]. Daily IP treatment with naringenin 50 mg/kg improved hematological indicators, including erythrocyte sedimentation rate, total white blood cell (WBC) count, differential WBC percentage, and platelet count [135]. Moreover, naringenin decreased the level of the pro-inflammatory cytokine, NF-κB [135]. Compared with diabetic rats that did not receive naringenin, those that received naringenin treatment showed decreased fasting blood sugar and glycated hemoglobin levels and increased serum insulin levels [136]. Hyperglycemia was induced by treating Chang cells with glucose, and naringenin treatment increased cell survival and reduced oxidative stress [137]. In an STZ-induced diabetes Sprague-Dawley rat model, naringenin treatment reduced the levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and oxidative stress [137]. When STZ-induced diabetic rats were fed a high-fat diet and subsequently treated with naringenin, hyperglycemia and hyperlipidemia were improved [138]. In addition, treatment with naringenin increased GLUT-4 expression and decreased TNF-α expression [138].
Steatosis and liver disease. Steatosis is characterized by fat accumulation in organs, such as the liver. The normal liver also contains fat but becomes impaired when the fat content exceeds 5% [139]. Nonalcoholic fatty liver disease (NAFLD) is divided into the early stage, nonalcoholic fatty liver (NAFL), and the worsening stage, nonalcoholic steatohepatitis [140]. NAFLD is related to metabolic syndrome, and more than one-third of patients with type 2 diabetes mellitus develop NAFLD [141, 142].
Naringenin inhibits fat accumulation in the liver, thereby alleviating liver diseases, including steatosis and NAFLD. In a mouse model of high-fat diet-induced obesity, naringenin treatment suppressed obesity [143]. Naringenin lowered hepatic TG levels and increased the expression of hepatic fatty acid oxidation and ketogenesis regulators, such as PGC1α [143]. In a mouse model of methionine–choline deficiency diet-induced NAFLD, naringenin suppressed hepatic lipid accumulation and inflammation by inhibiting NLRP3/NF-κB pathway activation [144]. In high-fat diet-induced NAFLD mice, treatment with naringenin activated AMPK inhibited autophagy and lipid accumulation and increased energy expenditure [145]. Furthermore, in high-fat diet-induced NAFLD mice, naringenin suppressed weight gain and reduced TG and total cholesterol levels in the liver and blood [146].
Atherosclerosis. Atherosclerosis is characterized by plaque accumulation in the lining of the arteries and; in severe cases, it can lead to stroke and myocardial infarction [147, 148]. Cholesterol mainly accumulates in the form of LDL [149]. If accumulation continues, blood flow decreases, and hypoxia occurs [149].
By improving blood lipid levels and suppressing plaque accumulation, naringenin suppresses atherosclerosis. Naringenin reduced aortic plaque deposits in a Western diet mouse model [150]. Additionally, naringenin decreased TG and total cholesterol levels [150]. Ldlr−/− mice fed a high-fat-cholesterol diet developed atherosclerosis, and naringenin treatment decreased plaque macrophages and increased smooth muscle cells [151]. By reducing plasma TG and cholesterol levels, naringenin inhibited plaque formation [151]. In ApoE−/− mice with atherosclerosis and vascular aging, naringenin suppressed the excessive production of ROS and increased the activity of antioxidant enzymes in the aorta [152]. Furthermore, the increased SIRT1 activity by naringenin increased the deacetylation and protein expression of the downstream factors, FOXO3a and PGC1α [152]. The administration of naringenin (FA-LNPs/Nrg), an oral nanomedicine made through FA-LNPs encapsulation, to ApoE−/− mice reduced the aortic lesion area and plaque areas [153]. Moreover, FA-LNPs/Nrg treatment reduced blood TG, total cholesterol, and LDL levels and increased HDL levels [153].
Neurodegenerative Diseases
Alzheimer’s disease. AD refers to chronic and persistent memory loss that causes cognitive impairment [154]. AD is characterized by the formation of amyloid plaques and neurofibrillary tangles composed of amyloid-beta (Aβ) and hyperphosphorylated tau [154, 155]. Acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and amyloid precursor protein cleaving enzyme 1 (BACE1) are essential enzymes responsible for AD development [156].
By regulating the PI3K/Akt/GSK-3β pathway and inhibiting AChE activity, naringenin suppresses memory loss. First, in AD-induced
Parkinson’s disease. PD is characterized by the loss of dopaminergic neurons in the midbrain [162]. PD causes motor disorders and may initially cause non-motor disorders, including anosmia, depression, and sleep disorders [163]. The regulation of neuroinflammation, dopamine, and oxidative stress play significant roles in PD [164]. 6-Hydroxydopamine (6-OHDA) is one of the neurotoxins used for inducing PD models by causing damage to dopamine neurons in the nigrostriatum [165]. Paraquat (PQ), a frequently used pesticide, induces oxidative stress and causes PD-like lesions in rodent animal models [166]. Rotenone-induced PD models can reproduce the main pathological features of clinical PD models [167].
Naringenin protects against oxidative damage caused by the PD inducers, including 6-OHDA, PQ, and rotenone. First, in 6-OHDA–induced
Conclusion and Future Prospects
Naringenin is a flavanone and is a well-known polyphenol. Naringenin has various physiological activities and has been shown to positively affect colorectal, gastric, lung, breast, ovarian, cervical, prostate, bladder, liver, pancreatic, and skin cancers. Moreover, naringenin has been shown to positively influence metabolic disorders, including diabetes, obesity, hyperlipidemia, hypertension, hyperglycemia, steatosis, liver disease, and atherosclerosis, as well as neurodegenerative diseases, including AD and PD.
According to clinicaltrials.gov, clinical studies on naringenin and citrus fruit extracts are actively underway. First, clinical studies using extracts have confirmed the safety and pharmacokinetics of naringenin. The serum naringenin concentration was confirmed after the oral administration of citrus extracts. Second, a clinical study using naringenin has been conducted. A study on whether naringenin can prevent hepatitis C virus infection and the effects of naringenin administration on subjective cognitive decline is ongoing. Furthermore, a study has investigated the effects of naringenin combined with β-carotene on energy consumption and glucose metabolism. In this manner, clinical trials on naringenin are actively underway.
These studies have suggested that naringenin can be implemented in clinical trials for the diseases introduced in this review. Overall, naringenin may become a promising preventive and therapeutic option for diseases threatening human health.
Acknowledgments
This work was supported by the National Research Foundation of Korea grant funded by the Korean government (MSIP) (NRF-2021R1C1C1013592).
Author Contributions
S.H.S. supervised the conception of the work. J.H.S. wrote the draft and S.H.S. revised it. All authors approved the final manuscript.
Conflict of Interest
The authors have no financial conflicts of interest to declare.
Fig 1.

Fig 2.

References
- (WHO). WHO. Cancer. Available online: https://www.who.int/news-room/fact-sheets/detail/cancer. (Accessed on 6 June, 2023).
- Rodriguez-Casado A. 2016. The health potential of fruits and vegetables phytochemicals: notable examples.
Crit. Rev. Food Sci. Nutr. 56 : 1097-1107. - Norat T, Scoccianti C, Boutron-Ruault MC, Anderson A, Berrino F, Cecchini M,
et al . 2015. European code against cancer 4th edition: diet and cancer.Cancer Epidemiol. 39 Suppl 1 : S56-66. - Guarente L. 2006. Sirtuins as potential targets for metabolic syndrome.
Nature 444 : 868-874. - Luo J, Si H, Jia Z, Liu D. 2021. Dietary anti-aging polyphenols and potential mechanisms.
Antioxidants (Basel) 10 : 283. - Santos AL, Lindner AB. 2017. Protein posttranslational modifications: roles in aging and age-related disease.
Oxid. Med. Cell. Longev. 2017 : 5716409. - Reith W. 2018. Neurodegenerative diseases.
Radiologe 58 : 241-258. - Li Z, Zhao T, Shi M, Wei Y, Huang X, Shen J,
et al . 2023. Polyphenols: natural food grade biomolecules for treating neurodegenerative diseases from a multi-target perspective.Front. Nutr. 10 : 1139558. - Patra S, Pradhan B, Nayak R, Behera C, Das S, Patra SK,
et al . 2021. Dietary polyphenols in chemoprevention and synergistic effect in cancer: clinical evidences and molecular mechanisms of action.Phytomedicine 90 : 153554. - Shohag S, Akhter S, Islam S, Sarker T, Sifat MK, Rahman MM,
et al . 2022. Perspectives on the molecular mediators of oxidative stress and antioxidant strategies in the context of neuroprotection and neurolongevity: an extensive review.Oxid. Med. Cell Longev. 2022 : 7743705. - Rivas F, Poblete-Aro C, Pando ME, Allel MJ, Fernandez V, Soto A,
et al . 2022. Effects of polyphenols in aging and neurodegeneration associated with oxidative stress.Curr. Med. Chem. 29 : 1045-1060. - Tufarelli V, Casalino E, D'Alessandro AG, Laudadio V. 2017. Dietary phenolic compounds: biochemistry, metabolism and significance in animal and human health.
Curr. Drug Metab. 18 : 905-913. - Teng H, Chen L. 2019. Polyphenols and bioavailability: an update.
Crit. Rev. Food Sci. Nutr. 59 : 2040-2051. - Di Lorenzo C, Colombo F, Biella S, Stockley C, Restani P. 2021. Polyphenols and human health: the role of bioavailability.
Nutrients 13 : 273. - Barreca D, Gattuso G, Bellocco E, Calderaro A, Trombetta D, Smeriglio A,
et al . 2017. Flavanones: citrus phytochemical with health-promoting properties.Biofactors 43 : 495-506. - Ramesh E, Alshatwi AA. 2013. Naringin induces death receptor and mitochondria-mediated apoptosis in human cervical cancer (SiHa) cells.
Food Chem. Toxicol. 51 : 97-105. - Esaki S, Nishiyama K, Sugiyama N, Nakajima R, Takao Y, Kamiya S. 1994. Preparation and taste of certain glycosides of flavanones and of dihydrochalcones.
Biosci. Biotechnol. Biochem. 58 : 1479-1485. - Shin W, Kim S, Chun KS. 1987. Structure of (R,S)-hesperetin monohydrate.
Acta Crystallogr. Sec. C. 43 : 1946-1949. - Tripoli E, La Guardia M, Giammanco S, Di Majo D, Giammanco M. 2007. Citrus flavonoids: molecular structure, biological activity and nutritional properties: a review.
Food Chem. 104 : 466-479. - Yao LH, Jiang YM, Shi J, TOMÁS-BARBERÁN FA, Datta N, Singanusong R,
et al . 2004. Flavonoids in food and their health benefits.Plant Foods Hum. Nutr. 59 : 113-122. - Graf BA, Milbury PE, Blumberg JB. 2005. Flavonols, flavones, flavanones, and human health: epidemiological evidence.
J. Med. Food 8 : 281-290. - Haytowitz DB, Wu X, Bhagwat S. USDA Database for the Flavonoid Content of Selected Foods, Release 3.3. U.S. Department of Agriculture, Agricultural Research Service, 2018. Nutrient Data Laboratory Home Page: http://www.ars.usda.gov/nutrientdata/flav..
- Ribeiro MH. 2011. Naringinases: occurrence, characteristics, and applications.
Appl. Microbiol. Biotechnol. 90 : 1883-1895. - Yusof S, Ghazali HM, King GS. 1990. Naringin content in local citrus fruits.
Food Chem. 37 : 113-121. - Zhang L, Song L, Zhang P, Liu T, Zhou L, Yang G,
et al . 2015. Solubilities of naringin and naringenin in different solvents and dissociation constants of naringenin.J. Chem. Eng. Data 60 : 932-940. - Justesen U, Knuthsen P, Leth T. 1998. Quantitative analysis of flavonols, flavones, and flavanones in fruits, vegetables and beverages by high-performance liquid chromatography with photo-diode array and mass spectrometric detection.
J. Chromatogr. A. 799 : 101-110. - Nait Chabane M, Al Ahmad A, Peluso J, Muller CD, Ubeaud G. 2009. Quercetin and naringenin transport across human intestinal Caco-2 cells.
J. Pharm. Pharmacol. 61 : 1473-1483. - Xu H, Kulkarni KH, Singh R, Yang Z, Wang SW, Tam VH,
et al . 2009. Disposition of naringenin via glucuronidation pathway is affected by compensating efflux transporters of hydrophilic glucuronides.Mol. Pharm. 6 : 1703-1715. - Kanaze FI, Bounartzi MI, Georgarakis M, Niopas I. 2007. Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects.
Eur. J. Clin. Nutr. 61 : 472-477. - Spencer JPE, Spencer JPE, Crozier A. 2012.
Flavonoids and Related Compounds : Bioavailability and Function , Ed. CRC Press, Hoboken. - Lin SP, Hou YC, Tsai SY, Wang MJ, Chao PD. 2014. Tissue distribution of naringenin conjugated metabolites following repeated dosing of naringin to rats.
Biomed. (Taipei) 4 : 16. - Youdim KA, Qaiser MZ, Begley DJ, Rice-Evans CA, Abbott NJ. 2004. Flavonoid permeability across an in situ model of the bloodbrain barrier.
Free Radic. Biol. Med. 36 : 592-604. - Youdim KA, Dobbie MS, Kuhnle G, Proteggente AR, Abbott NJ, Rice-Evans C. 2003. Interaction between flavonoids and the blood-brain barrier: in vitro studies.
J. Neurochem. 85 : 180-192. - Peng HW, Cheng FC, Huang YT, Chen CF, Tsai TH. 1998. Determination of naringenin and its glucuronide conjugate in rat plasma and brain tissue by high-performance liquid chromatography.
J. Chromatogr. B Biomed. Sci. Appl. 714 : 369-374. - Zeng X, Su W, Zheng Y, He Y, He Y, Rao H,
et al . 2019. Pharmacokinetics, tissue distribution, metabolism, and excretion of naringin in aged rats.Front. Pharmacol. 10 : 34. - Chen T, Wu H, He Y, Pan W, Yan Z, Liao Y,
et al . 2019. Simultaneously quantitative analysis of naringin and its major human gut microbial metabolites naringenin and 3-(4'-Hydroxyphenyl) propanoic acid via stable isotope deuterium-labeling coupled with RRLC-MS/MS method.Molecules 24 : 4287. - Braune A, Gutschow M, Blaut M. 2019. An NADH-dependent reductase from
Eubacterium ramulus catalyzes the stereospecific heteroring cleavage of flavanones and flavanonols.Appl.Environ. Microbiol. 85 : e01233-19. - Jeon SM, Kim HK, Kim HJ, Do GM, Jeong TS, Park YB,
et al . 2007. Hypocholesterolemic and antioxidative effects of naringenin and its two metabolites in high-cholesterol fed rats.Transl. Res. 149 : 15-21. - Pereira-Caro G, Oliver CM, Weerakkody R, Singh T, Conlon M, Borges G,
et al . 2015. Chronic administration of a microencapsulated probiotic enhances the bioavailability of orange juice flavanones in humans.Free Radic. Biol. Med. 84 : 206-214. - Ranka S, Gee JM, Biro L, Brett G, Saha S, Kroon P,
et al . 2008. Development of a food frequency questionnaire for the assessment of quercetin and naringenin intake.Eur. J. Clin. Nutr. 62 : 1131-1138. - Xu HY, Kulkarni KH, Singh R, Yang Z, Wang SWJ, Tam VH,
et al . 2009. Disposition of naringenin via glucuronidation pathway is affected by compensating efflux transporters of hydrophilic glucuronides.Mol. Pharm. 6 : 1703-1715. - Torre LA, Siegel RL, Ward EM, Jemal A. 2016. Global cancer incidence and mortality rates and trends--An update.
Cancer Epidemiol. Biomarkers Prev. 25 : 16-27. - Kawaii S, Tomono Y, Katase E, Ogawa K, Yano M. 1999. Antiproliferative effects of the readily extractable fractions prepared from various citrus juices on several cancer cell lines.
J. Agric.Food Chem. 47 : 2509-2512. - KAWAII S, TOMONO Y, KATASE E, OGAWA K, YANO M. 1999. Antiproliferative activity of flavonoids on several cancer cell lines.
Biosci. Biotechnol. Biochem. 63 : 896-899. - Siegel RL, Miller KD, Wagle NS, Jemal A. 2023. Cancer statistics, 2023.
CA Cancer J. Clin. 73 : 17-48. - Rajamanickam S, Agarwal R. 2008. Natural products and colon cancer: current status and future prospects.
Drug Dev. Res. 69 : 460-471. - Frydoonfar HR, McGrath DR, Spigelman AD. 2003. The variable effect on proliferation of a colon cancer cell line by the citrus fruit flavonoid Naringenin.
Colorectal. Dis. 5 : 149-152. - Zhao Y, Fan D, Ru B, Cheng K-W, Hu S, Zhang J,
et al . 2016. 6-C-(E-phenylethenyl)naringenin induces cell growth inhibition and cytoprotective autophagy in colon cancer cells.Eur. J. Cancer 68 : 38-50. - Song HM, Park GH, Bo HJ, Lee JW, Kim MK, Lee JR,
et al . 2015. Anti-proliferative effect of naringenin through p38-dependent downregulation of cyclin D1 in human colorectal cancer cells.Biomol. Ther. 23 : 339-344. - Raeisi S, Chavoshi H, Mohammadi M, Ghorbani M, Sabzichi M, Ramezani F. 2019. Naringenin-loaded nano-structured lipid carrier fortifies oxaliplatin-dependent apoptosis in HT-29 cell line.
Process Biochem. 83 : 168-175. - Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A,
et al . 2021. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J. Clin. 71 : 209-249. - Tan P, Yeoh KG. 2015. Genetics and molecular pathogenesis of gastric adenocarcinoma.
Gastroenterology 149 : 1153-1162 e1153. - Tramacere I, Negri E, Pelucchi C, Bagnardi V, Rota M, Scotti L,
et al . 2012. A meta-analysis on alcohol drinking and gastric cancer risk.Ann. Oncol. 23 : 28-36. - Lordick F, Carneiro F, Cascinu S, Fleitas T, Haustermans K, Piessen G,
et al . 2022. Gastric cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up.Ann. Oncol. 33 : 1005-1020. - Lu L, Mullins CS, Schafmayer C, Zeissig S, Linnebacher M. 2021. A global assessment of recent trends in gastrointestinal cancer and lifestyle-associated risk factors.
Cancer Commun (Lond) 41 : 1137-1151. - Bao L, Liu F, Guo HB, Li Y, Tan BB, Zhang WX,
et al . 2016. Naringenin inhibits proliferation, migration, and invasion as well as induces apoptosis of gastric cancer SGC7901 cell line by downregulation of AKT pathway.Tumor Biol. 37 : 11365-11374. - Lahiri A, Maji A, Potdar PD, Singh N, Parikh P, Bisht B,
et al . 2023. Lung cancer immunotherapy: progress, pitfalls, and promises.Mol. Cancer 22 : 40. - Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. 2018. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
CA Cancer J. Clin. 68 : 394-424. - Kanwal M, Ding XJ, Cao Y. 2017. Familial risk for lung cancer (Review).
Onco. Lett. 13 : 535-542. - Qin L, Jin L, Lu L, Lu X, Zhang C, Zhang F,
et al . 2011. Naringenin reduces lung metastasis in a breast cancer resection model.Protein Cell 2 : 507-516. - Du G, Jin L, Han X, Song Z, Zhang H, Liang W. 2009. Naringenin: a potential immunomodulator for inhibiting lung fibrosis and metastasis.
Cancer Res. 69 : 3205-3212. - Chang HL, Chang YM, Lai SC, Chen KM, Wang KC, Chiu TT,
et al . 2017. Naringenin inhibits migration of lung cancer cells via the inhibition of matrix metalloproteinases-2 and -9.Exp. Ther. Med. 13 : 739-744. - Jin CY, Park C, Hwang HJ, Kim GY, Choi BT, Kim WJ,
et al . 2011. Naringenin up-regulates the expression of death receptor 5 and enhances TRAIL-induced apoptosis in human lung cancer A549 cells.Mol. Nutr. Food Res. 55 : 300-309. - Liu X, Zhao T, Shi Z, Hu C, Li Q, Sun C. 2023. Synergism antiproliferative effects of apigenin and naringenin in NSCLC cells.
Molecules 28 : 4947. - Pateliya B, Burade V, Goswami S. 2021. Combining naringenin and metformin with doxorubicin enhances anticancer activity against triple-negative breast cancer in vitro and in vivo.
Eur. J. Pharmacol. 891 : 173725. - Noori S, Nourbakhsh M, Imani H, Deravi N, Salehi N, Abdolvahabi Z. 2022. Naringenin and cryptotanshinone shift the immune response towards Th1 and modulate T regulatory cells via JAK2/STAT3 pathway in breast cancer.
BMC Complement. Med. Ther. 22 : 145. - Zhang F, Dong W, Zeng W, Zhang L, Zhang C, Qiu Y,
et al . 2016. Naringenin prevents TGF-beta1 secretion from breast cancer and suppresses pulmonary metastasis by inhibiting PKC activation.Breast Cancer Res. 18 : 38. - Wang R, Wang JH, Dong TF, Shen J, Gao XT, Zhou J. 2019. Naringenin has a chemoprotective effect in MDA-MB-231 breast cancer cells via inhibition of caspase-3 and-9 activities.
Oncol. Lett. 17 : 1217-1222. - Harmon AW, Patel YM. 2004. Naringenin inhibits glucose uptake in MCF-7 breast cancer cells: a mechanism for impaired cellular proliferation.
Breast Cancer Res. Treat. 85 : 103-110. - Sun Y, Gu J. 2015. [Study on effect of naringenin in inhibiting migration and invasion of breast cancer cells and its molecular mechanism].
Zhongguo Zhong Yao Za Zhi. 40 : 1144-1150. - Jayson GC, Kohn EC, Kitchener HC, Ledermann JA. 2014. Ovarian cancer.
Lancet 384 : 1376-1388. - Lin C, Zeng Z, Lin Y, Wang P, Cao D, Xie K,
et al . 2022. Naringenin suppresses epithelial ovarian cancer by inhibiting proliferation and modulating gut microbiota.Phytomedicine 106 : 154401. - Cohen PA, Jhingran A, Oaknin A, Denny L. 2019. Cervical cancer.
Lancet 393 : 169-182. - Krishnakumar N, Sulfikkarali N, RajendraPrasad N, Karthikeyan S. 2011. Enhanced anticancer activity of naringenin-loaded nanoparticles in human cervical (HeLa) cancer cells.
Biomed. Prevent. Nutr. 1 : 223-231. - Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M,
et al . 2015. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.Int. J. Cancer 136 : E359-E386. - Liao ACH, Kuo CC, Huang YC, Yeh CW, Hseu YC, Liu JY,
et al . 2014. Naringenin inhibits migration of bladder cancer cells through downregulation of AKT and MMP-2.Mol. Med. Rep. 10 : 1531-1536. - Nguyen-Nielsen M, Borre M. 2016. Diagnostic and therapeutic strategies for prostate cancer.
Semin. Nucl. Med. 46 : 484-490. - Han KY, Chen PN, Hong MC, Hseu YC, Chen KM, Hsu LS,
et al . 2018. Naringenin attenuated prostate cancer invasion via reversal of epithelial-to-mesenchymal transition and inhibited uPA activity.Anticancer Res. 38 : 6753-6758. - Gumushan Aktas H, Akgun T. 2018. Naringenin inhibits prostate cancer metastasis by blocking voltage-gated sodium channels.
Biomed Pharmacother. 106 : 770-775. - Lim W, Park S, Bazer FW, Song G. 2016. Naringenin-induced apoptotic cell death in prostate cancer cells is mediated via the PI3K/AKT and MAPK signaling pathways.
J. Cell. Biochem. 118 : 1118-1131. - Yang YM, Kim SY, Seki E. 2019. Inflammation and liver cancer: molecular mechanisms and therapeutic targets.
Semin. Liver Dis. 39 : 26-42. - Arul D, Subramanian P. 2013. Inhibitory effect of naringenin (citrus flavonone) on N-nitrosodiethylamine induced hepatocarcinogenesis in rats.
Biochem. Biophys. Res. Commun. 434 : 203-209. - Thangavel P, Vaiyapuri M. 2013. Antiproliferative and apoptotic effects of naringin on diethylnitrosamine induced hepatocellular carcinoma in rats.
Biomed. Aging Pathol. 3 : 59-64. - Yen HR, Liu CJ, Yeh CC. 2015. Naringenin suppresses TPA-induced tumor invasion by suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells.
Chem. Biol. Interact. 235 : 1-9. - Kang Q, Gong J, Wang M, Wang Q, Chen F, Cheng K-W. 2019. 6-C-(E-Phenylethenyl)Naringenin attenuates the stemness of hepatocellular carcinoma cells by suppressing Wnt/β-catenin signaling.
J. Agric. Food Chem. 67 : 13939-13947. - Pan P, Huang YW, Oshima K, Yearsley M, Zhang J, Yu J,
et al . 2018. An immunological perspective for preventing cancer with berries.J. Berry Res. 8 : 163-175. - Lou C, Zhang F, Yang M, Zhao J, Zeng W, Fang X,
et al . 2012. Naringenin decreases invasiveness and metastasis by inhibiting TGFbeta-induced epithelial to mesenchymal transition in pancreatic cancer cells.PLoS One 7 : e50956. - Lee J, Kim DH, Kim JH. 2019. Combined administration of naringenin and hesperetin with optimal ratio maximizes the anticancer effect in human pancreatic cancer via down regulation of FAK and p38 signaling pathway.
Phytomedicine 58 : 152762. - Park HJ, Choi YJ, Lee JH, Nam MJ. 2017. Naringenin causes ASK1-induced apoptosis via reactive oxygen species in human pancreatic cancer cells.
Food Chem. Toxicol. 99 : 1-8. - Force USPST, Mangione CM, Barry MJ, Nicholson WK, Chelmow D, Coker TR,
et al . 2023. Screening for skin cancer: US preventive services task force recommendation statement.JAMA 329 : 1290-1295. - Ahamad MS, Siddiqui S, Jafri A, Ahmad S, Afzal M, Arshad M. 2014. Induction of apoptosis and antiproliferative activity of naringenin in human epidermoid carcinoma cell through ROS generation and cell cycle arrest.
PLoS One 9 : e110003. - Kumar R, Bhan Tiku A. 2020. Naringenin suppresses chemically induced skin cancer in two-stage skin carcinogenesis mouse model.
Nutr. Cancer 72 : 976-983. - Pafumi I, Festa M, Papacci F, Lagostena L, Giunta C, Gutla V,
et al . 2017. Naringenin impairs two-pore channel 2 activity and inhibits VEGF-induced angiogenesis.Sci. Rep. 7 : 5121. - Manna P, Das J, Ghosh J, Sil PC. 2010. Contribution of type 1 diabetes to rat liver dysfunction and cellular damage via activation of NOS, PARP, IkappaBalpha/NF-kappaB, MAPKs, and mitochondria-dependent pathways: prophylactic role of arjunolic acid.
Free Radic. Biol. Med. 48 : 1465-1484. - Zhang C, Lu XM, Tan Y, Li B, Miao X, Jin LT,
et al . 2012. Diabetes-induced hepatic pathogenic damage, inflammation, oxidative stress, and insulin resistance was exacerbated in zinc deficient mouse model.PLoS One 7 : e49257. - Gowd V, Nandini CD. 2015. Erythrocytes in the combined milieu of high glucose and high cholesterol shows glycosaminoglycandependent cytoadherence to extracellular matrix components.
Int. J. Biol. Macromol. 73 : 182-188. - Joladarashi D, Salimath PV, Chilkunda ND. 2011. Diabetes results in structural alteration of chondroitin sulfate/dermatan sulfate in the rat kidney: effects on the binding to extracellular matrix components.
Glycobiology 21 : 960-972. - Ritz E. 2006. Diabetic nephropathy.
Saudi J. Kidney Dis. Transpl. 17 : 481-490. - Kam J, Puranik S, Yadav R, Manwaring HR, Pierre S, Srivastava RK,
et al . 2016. Dietary interventions for type 2 diabetes: how millet comes to help.Front. Plant Sci. 7 : 1454. - Ortiz-Andrade RR, Sanchez-Salgado JC, Navarrete-Vazquez G, Webster SP, Binnie M, Garcia-Jimenez S,
et al . 2008. Antidiabetic and toxicological evaluations of naringenin in normoglycaemic and NIDDM rat models and its implications on extra-pancreatic glucose regulation.Diabetes Obes. Metab. 10 : 1097-1104. - Tsai SJ, Huang CS, Mong MC, Kam WY, Huang HY, Yin MC. 2012. Anti-inflammatory and antifibrotic effects of naringenin in diabetic mice.
J. Agric. Food Chem. 60 : 514-521. - Orsolic N, Gajski G, Garaj-Vrhovac V, Dikic D, Prskalo ZS, Sirovina D. 2011. DNA-protective effects of quercetin or naringenin in alloxan-induced diabetic mice.
Eur. J. Pharmacol. 656 : 110-118. - Kannappan S, Anuradha CV. 2010. Naringenin enhances insulin-stimulated tyrosine phosphorylation and improves the cellular actions of insulin in a dietary model of metabolic syndrome.
Eur. J. Nutr. 49 : 101-109. - Priscilla DH, Roy D, Suresh A, Kumar V, Thirumurugan K. 2014. Naringenin inhibits alpha-glucosidase activity: a promising strategy for the regulation of postprandial hyperglycemia in high fat diet fed streptozotocin induced diabetic rats.
Chem. Biol. Interact. 210 : 77-85. - Mutlur Krishnamoorthy R, Carani Venkatraman A. 2017. Polyphenols activate energy sensing network in insulin resistant models.
Chem. Biol. Interact. 275 : 95-107. - Burke AC, Telford DE, Edwards JY, Sutherland BG, Sawyez CG, Huff MW. 2019. Naringenin supplementation to a chow Diet enhances energy expenditure and fatty acid oxidation, and reduces adiposity in lean, pair-fed Ldlr(-/-) mice.
Mol. Nutr. Food Res. 63 : e1800833. - Zygmunt K, Faubert B, MacNeil J, Tsiani E. 2010. Naringenin, a citrus flavonoid, increases muscle cell glucose uptake via AMPK.
Biochem. Biophys. Res. Commun. 398 : 178-183. - Bhattacharya S, Oksbjerg N, Young JF, Jeppesen PB. 2014. Caffeic acid, naringenin and quercetin enhance glucose-stimulated insulin secretion and glucose sensitivity in INS-1E cells.
Diabetes Obes. Metab. 16 : 602-612. - von dem Knesebeck O, Lüdecke D, Luck-Sikorski C, Kim TJ. 2019. Public beliefs about causes of obesity in the USA and in Germany.
Int. J.Public Health 64 : 1139-1146. - Ruhm CJ. 2012. Understanding overeating and obesity.
J. Health Economics 31 : 781-796. - Lu SX, Wu TW, Chou CL, Cheng CF, Wang LY. 2023. Combined effects of hypertension, hyperlipidemia, and diabetes mellitus on the presence and severity of carotid atherosclerosis in community-dwelling elders: a community-based study.
J. Chin. Med. Assoc. 86 : 220-226. - Engin A. 2017. The definition and prevalence of obesity and metabolic syndrome.
Adv. Exp. Med. Biol. 960 : 1-17. - Klop B, Elte JW, Cabezas MC. 2013. Dyslipidemia in obesity: mechanisms and potential targets.
Nutrients 5 : 1218-1240. - Rakhra V, Galappaththy SL, Bulchandani S, Cabandugama PK. 2020. Obesity and the Western diet: how We got here.
Mo Med. 117 : 536-538. - Lee SH, Park YB, Bae KH, Bok SH, Kwon YK, Lee ES,
et al . 1999. Cholesterol-lowering activity of naringenin via inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase and acyl coenzyme A:cholesterol acyltransferase in rats.Ann. Nutr. Metab. 43 : 173-180. - Cho KW, Kim YO, Andrade JE, Burgess JR, Kim YC. 2011. Dietary naringenin increases hepatic peroxisome proliferators-activated receptor alpha protein expression and decreases plasma triglyceride and adiposity in rats.
Eur. J. Nutr. 50 : 81-88. - Zar Kalai F, Han J, Ksouri R, El Omri A, Abdelly C, Isoda H. 2013. Antiobesity effects of an edible halophyte Nitraria retusa forssk in 3T3-L1 preadipocyte differentiation and in C57B6J/L mice fed a high fat diet-induced obesity.
Evid. Based Complement. Alternat. Med. 2013 : 368658. - Yoshida H, Watanabe W, Oomagari H, Tsuruta E, Shida M, Kurokawa M. 2013. Citrus flavonoid naringenin inhibits TLR2 expression in adipocytes.
J. Nutr. Biochem. 24 : 1276-1284. - Cai XY, Wang SX, Wang HL, Liu SW, Liu GS, Chen HB,
et al . 2023. Naringenin inhibits lipid accumulation by activating the AMPK pathway in vivo and in vitro.Food Sci. Hum. Wellness 12 : 1174-1183. - Assini JM, Mulvihill EE, Sutherland BG, Telford DE, Sawyez CG, Felder SL,
et al . 2013. Naringenin prevents cholesterol-induced systemic inflammation, metabolic dysregulation, and atherosclerosis in Ldlr(-)/(-) mice.J. Lipid Res. 54 : 711-724. - Mulvihill EE, Allister EM, Sutherland BG, Telford DE, Sawyez CG, Edwards JY,
et al . 2009. Naringenin prevents dyslipidemia, apolipoprotein B overproduction, and hyperinsulinemia in LDL receptor-null mice with diet-induced insulin resistance.Diabetes 58 : 2198-2210. - Richard AJ, Amini-Vaughan Z, Ribnicky DM, Stephens JM. 2013. Naringenin inhibits adipogenesis and reduces insulin sensitivity and adiponectin expression in adipocytes.
Evid. Based. Complement. Alternat. Med. 2013 : 549750. - Mills KT, Stefanescu A, He J. 2020. The global epidemiology of hypertension.
Nat. Rev. Nephrol. 16 : 223-237. - Mowry FE, Biancardi VC. 2019. Neuroinflammation in hypertension: the renin-angiotensin system versus pro-resolution pathways.
Pharmacol. Res. 144 : 279-291. - Carey RM, Muntner P, Bosworth HB, Whelton PK. 2018. Prevention and control of hypertension: JACC health promotion series.
J. Am. Coll. Cardiol. 72 : 1278-1293. - Liu H, Zhao H, Che J, Yao W. 2022. Naringenin protects against hypertension by regulating lipid disorder and oxidative stress in a rat model.
Kidney Blood Press Res. 47 : 423-432. - Duan B, Li Y, Geng H, Ma A, Yang X. 2021. Naringenin prevents pregnancy-induced hypertension via suppression of JAK/STAT3 signalling pathway in mice.
Int. J. Clin. Pract. 75 : e14509. - Wang Z, Wang S, Zhao J, Yu C, Hu Y, Tu Y,
et al . 2019. Naringenin ameliorates renovascular hypertensive renal damage by normalizing the balance of renin-angiotensin system components in rats.Int. J. Med. Sci. 16 : 644-653. - Ademola Adetokunbo Oyagbemi, Temidayo Olutayo Omobowale, Olumuyiwa Abiola Adejumobi, Abiodun Mary Owolabi, Blessing Seun Ogunpolu, Olufunke Olubunmi Falayi,
et al . 2020. Antihypertensive power of Naringenin is mediated via attenuation of mineralocorticoid receptor (MCR)/angiotensin converting enzyme (ACE)/kidney injury molecule (Kim-1) signaling pathway.Eur. J. Pharmacol. 880 : 173142. - Hammer M, Storey S, Hershey DS, Brady VJ, Davis E, Mandolfo N,
et al . 2019. Hyperglycemia and cancer: a state-of-the-science review.Oncol. Nurs. Forum. 46 : 459-472. - Villegas-Valverde CC, Kokuina E, Breff-Fonseca MC. 2018. Strengthening national health priorities for diabetes prevention and management.
MEDICC Rev. 20 : 5. - Mouri M, Badireddy M. 2023. Hyperglycemia, pp.,
StatPearls , Ed., Treasure Island (FL). - Yari Z, Behrouz V, Zand H, Pourvali K. 2020. New insight into diabetes management: from glycemic index to dietary insulin index.
Curr. Diab. Rev. 16 : 293-300. - Rawlings AM, Sharrett AR, Albert MS, Coresh J, Windham BG, Power MC,
et al . 2019. The association of late-life diabetes status and hyperglycemia with incident mild cognitive impairment and dementia: the ARIC study.Diab. Care 42 : 1248-1254. - Annadurai T, Thomas PA, Geraldine P. 2013. Ameliorative effect of naringenin on hyperglycemia-mediated inflammation in hepatic and pancreatic tissues of Wistar rats with streptozotocin- nicotinamide-induced experimental diabetes mellitus.
Free Radic. Res. 47 : 793-803. - Annadurai T, Muralidharan AR, Joseph T, Hsu MJ, Thomas PA, Geraldine P. 2012. Antihyperglycemic and antioxidant effects of a flavanone, naringenin, in streptozotocin-nicotinamide-induced experimental diabetic rats.
J. Physiol. Biochem. 68 : 307-318. - Kometsi L, Govender K, Mofo Mato EP, Hurchund R, Owira PMO. 2020. By reducing oxidative stress, naringenin mitigates hyperglycaemia-induced upregulation of hepatic nuclear factor erythroid 2-related factor 2 protein.
J. Pharm. Pharmacol. 72 : 1394-1404. - Priscilla DH, Jayakumar M, Thirumurugan K. 2015. Flavanone naringenin: an effective antihyperglycemic and antihyperlipidemic nutraceutical agent on high fat diet fed streptozotocin induced type 2 diabetic rats.
J. Funct. Foods 14 : 363-373. - Bortz JH. 2023. Metabolic-associated fatty liver disease: opportunistic screening at CT colonography.
CT Colonography for Radiographers . pp. 277-290. - Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, Abdelmalek MF, Caldwell S, Barb D,
et al . 2023. AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease.Hepatology 77 : 1797-1835. - Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M,
et al . 2018. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.Nat. Rev. Gastroenterol. Hepatol. 15 : 11-20. - Adams LA, Harmsen S, St Sauver JL, Charatcharoenwitthaya P, Enders FB, Therneau T,
et al . 2010. Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: a community-based cohort study.Am. J. Gastroenterol. 105 : 1567-1573. - Assini JM, Mulvihill EE, Burke AC, Sutherland BG, Telford DE, Chhoker SS,
et al . 2015. Naringenin prevents obesity, hepatic steatosis, and glucose intolerance in male mice independent of fibroblast growth factor 21.Endocrinology 156 : 2087-2102. - Wang Q, Ou Y, Hu G, Wen C, Yue S, Chen C,
et al . 2020. Naringenin attenuates non-alcoholic fatty liver disease by down-regulating the NLRP3/NF-kappaB pathway in mice.Br. J. Pharmacol. 177 : 1806-1821. - Yang Y, Wu Y, Zou J, Wang YH, Xu MX, Huang W,
et al . 2021. Naringenin attenuates non-alcoholic fatty liver disease by enhancing energy expenditure and regulating Autophagy via AMPK.Front. Pharmacol. 12 : 687095. - Yu RY, Gu YP, Zheng LY, Liu ZJ, Bian YF. 2023. Naringenin prevents NAFLD in the diet-induced C57BL/6J obesity model by regulating the intestinal barrier function and microbiota.
J. Funct. Foods 105 : 105578. - Kruk ME, Gage AD, Joseph NT, Danaei G, García-Saisó S, Salomon JA. 2018. Mortality due to low-quality health systems in the universal health coverage era: a systematic analysis of amenable deaths in 137 countries.
Lancet 392 : 2203-2212. - Blagov AV, Markin AM, Bogatyreva AI, Tolstik TV, Sukhorukov VN, Orekhov AN. 2023. The role of macrophages in the pathogenesis of atherosclerosis.
Cells 12 : 522. - Wolf D, Ley K. 2019. Immunity and inflammation in atherosclerosis.
Circ. Res. 124 : 315-327. - Mulvihill EE, Assini JM, Sutherland BG, DiMattia AS, Khami M, Koppes JB,
et al . 2010. Naringenin decreases progression of atherosclerosis by improving dyslipidemia in high-fat-fed low-density lipoprotein receptor-null mice.Arterioscler. Thromb. Vasc. Biol. 30 : 742-U224. - Burke AC, Sutherland BG, Telford DE, Morrow MR, Sawyez CG, Edwards JY,
et al . 2019. Naringenin enhances the regression of atherosclerosis induced by a chow diet in Ldlr(-/-) mice.Atherosclerosis 286 : 60-70. - Wang J, Wu R, Hua Y, Ling S, Xu X. 2023. Naringenin ameliorates vascular senescence and atherosclerosis involving SIRT1 activation.
J. Pharm. Pharmacol. 75 : 1021-1033. - Guo MR, He ZS, Jin ZH, Huang LJ, Yuan JM, Qin SG,
et al . 2023. Oral nanoparticles containing naringenin suppress atherosclerotic progression by targeting delivery to plaque macrophages.Nano Res. 16 : 925-937. - Graham WV, Bonito-Oliva A, Sakmar TP. 2017. Update on Alzheimer's disease therapy and prevention strategies.
Annu. Rev. Med. 68 : 413-430. - Rajmohan R, Reddy PH. 2017. Amyloid-beta and phosphorylated Tau accumulations cause abnormalities at synapses of Alzheimer's disease neurons.
J. Alzheimers Dis. 57 : 975-999. - Tamagno E, Bardini P, Obbili A, Vitali A, Borghi R, Zaccheo D,
et al . 2002. Oxidative stress increases expression and activity of BACE in NT2 neurons.Neurobiol. Dis. 10 : 279-288. - Yang W, Ma J, Liu Z, Lu Y, Hu B, Yu H. 2014. Effect of naringenin on brain insulin signaling and cognitive functions in ICV-STZ induced dementia model of rats.
Neurol. Sci. 35 : 741-751. - Zhang N, Hu ZH, Zhang ZB, Liu GL, Wang YQ, Ren YD,
et al . 2018. Protective role of Naringenin against Aβ -caused damage via ER and PI3K/Akt-mediated pathways.Cell. Mol. Neurobiol. 38 : 549-557. - Heo HJ, Kim MJ, Lee JM, Choi SJ, Cho HY, Hong B,
et al . 2004. Naringenin from citrus junos has an inhibitory effect on acetylcholinesterase and a mitigating effect on amnesia.Dement. Geriatr. Cogn. Disord. 17 : 151-157. - Lee S, Youn K, Lim G, Lee J, Jun M. 2018. In silico docking and in vitro approaches towards BACE1 and cholinesterases inhibitory effect of citrus flavanones.
Molecules 23 : 1509. - Ghofrani S, Joghataei MT, Mohseni S, Baluchnejadmojarad T, Bagheri M, Khamse S,
et al . 2015. Naringenin improves learning and memory in an Alzheimer's disease rat model: insights into the underlying mechanisms.Eur. J. Pharmacol. 764 : 195-201. - Zella MAS, Metzdorf J, Ostendorf F, Maass F, Muhlack S, Gold R,
et al . 2019. Novel immunotherapeutic approaches to target alphasynuclein and related neuroinflammation in Parkinson's disease.Cells 8 : 105. - Sung VW, Nicholas AP. 2013. Nonmotor symptoms in Parkinson's disease: expanding the view of Parkinson's disease beyond a pure motor, pure dopaminergic problem.
Neurol. Clin. 31 : S1-16. - Jayaraj RL, Beiram R, Azimullah S, Meeran MFN, Ojha SK, Adem A,
et al . 2019. Lycopodium attenuates loss of dopaminergic neurons by suppressing oxidative stress and neuroinflammation in a rat model of Parkinson's disease.Molecules 24 : 2182. - Simola N, Morelli M, Carta AR. 2007. The 6-hydroxydopamine model of Parkinson's disease.
Neurotox Res. 11 : 151-167. - Berry C, La Vecchia C, Nicotera P. 2010. Paraquat and Parkinson's disease.
Cell Death Differ. 17 : 1115-1125. - Cannon JR, Tapias V, Na HM, Honick AS, Drolet RE, Greenamyre JT. 2009. A highly reproducible rotenone model of Parkinson's disease.
Neurobiol. Dis. 34 : 279-290. - Lou H, Jing X, Wei X, Shi H, Ren D, Zhang X. 2014. Naringenin protects against 6-OHDA-induced neurotoxicity via activation of the Nrf2/ARE signaling pathway.
Neuropharmacology 79 : 380-388. - Zbarsky V, Datla KP, Parkar S, Rai DK, Aruoma OI, Dexter DT. 2005. Neuroprotective properties of the natural phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson's disease.
Free Radic. Res. 39 : 1119-1125. - Ahmad MH, Fatima M, Ali M, Rizvi MA, Mondal AC. 2021. Naringenin alleviates paraquat-induced dopaminergic neuronal loss in SH-SY5Y cells and a rat model of Parkinson's disease.
Neuropharmacology 201 : 108831. - Dashputre NL, Laddha UD, Pagare TD, Kadam JD, Patil SB, Tajanpure AB,
et al . 2023. Fabrication of nanoparticulate system for oral delivery of Naringenin against paraquat-induced Parkinson's disorder in Wistar rats.Eur. J. Med. Chem. Rep. 8 : 100105. - Madiha S, Batool Z, Shahzad S, Tabassum S, Liaquat L, Afzal A,
et al . 2023. Naringenin, a functional food component, improves motor and non-motor symptoms in animal model of parkinsonism induced by rotenone.Plant Foods Hum. Nutr. 78 : 654-661. - Sonia Angeline M, Sarkar A, Anand K, Ambasta RK, Kumar P. 2013. Sesamol and naringenin reverse the effect of rotenone-induced PD rat model.
Neuroscience 254 : 379-394.