• PM(2.5)
• antioxidant
• endogenous protein
• lung injury
• metallothionein
• oxidative stress

• Animals
• Metallothionein/metabolism
• Metallothionein/genetics
• Antioxidants/metabolism
• Antioxidants/pharmacology
• Acute Lung Injury/chemically induced
• Acute Lung Injury/prevention & control
• Acute Lung Injury/metabolism
• Acute Lung Injury/pathology
• Air Pollutants/toxicity
• Mice, Knockout
• Mice
• Mice, Inbred C57BL
• Reactive Oxygen Species/metabolism
• Male
• Oxidative Stress/drug effects
• Lung/metabolism
• Lung/pathology
• Lung/drug effects

• cholecystokinin
• ghrelin
• high-fat diet
• hunger
• obesity
• phenolic compounds
• satiety

• Acetaminophen
• Acute liver injury
• Naringenin
• Network pharmacology
• PPARA

• Humans
• Animals
• Mice
• Liver/metabolism
• Signal Transduction
• Hepatocytes/metabolism
• Inflammation/metabolism
• Oxidative Stress
• Chemical and Drug Induced Liver Injury/metabolism
• Flavanones

• Lactiplantibacillus plantarum
• broiler liver
• endoplasmic reticulum stress
• oxidative stress
• proteomics

• antioxidant
• dasatinib
• hepatotoxicity
• inflammation
• naringenin
• protective effects

• RSPD2023R563 King Saud University

• apoptosis
• hawthorn fruit extract
• microcystin-LR
• oxidative stress
• protection

• 81903314 National Natural Science Foundation of China

• Acetaminophen
• Hepatotoxicity
• Herbal formulations
• Natural products
• Phytoconstituents
• Plant extracts

• Mice
• Animals
• Acetaminophen/adverse effects
• Chemical and Drug Induced Liver Injury/drug therapy
• Chemical and Drug Induced Liver Injury/prevention & control
• Chemical and Drug Induced Liver Injury/metabolism
• Biological Products/pharmacology
• Mice, Inbred C57BL
• Liver
• Plant Extracts/pharmacology
• Plant Extracts/metabolism

Although the pathogenesis of chronic obstructive pulmonary disease (COPD) is not yet fully understood, recent studies suggest that the disruption of the intracellular balance of oxidative (such as reactive oxygen species (ROS)) and antioxidant molecules plays an important role in COPD development and progression. Metallothionein is an endogenous metal-binding protein with reported ROS scavenging activity. Although there have been many publications on the protective effects of metallothionein in the kidney and liver, its role in COPD models such as elastase- or cigarette smoke (CS)-induced lung injury is unknown. Thus, in the present study, we analyzed the elastase-induced lung injury model using metallothionein-knockout (MT-KO; MT-1 and -2 gene deletion) mice. The expression of MT-1 and MT-2 in the lungs of MT-KO mice was markedly lower compared with that in the lungs of wildtype (WT) mice. Porcine pancreatic elastase (PPE)-induced lung injury (alveolar enlargement and respiratory impairment) was significantly exacerbated in MT-KO mice compared with WT mice. Additionally, PPE-induced increases in the number of inflammatory cells, inflammatory cytokines, and cell death in lung tissue were significantly more pronounced in MT-KO mice compared with WT mice. Finally, using an in vivo imaging system, we also found that PPE-induced ROS production in the lungs was enhanced in MT-KO mice compared with WT mice. These results suggest that metallothionein may act as an inhibitor against elastase-induced lung injury by suppressing ROS production. These results suggest that metallothionein protein, or compounds that can induce metallothionein, could be useful in the treatment of COPD.

• Antioxidant
• Bangladeshi medicinal plants
• Bioactive compounds
• Ethnomedicine
• Hepatic disorders
• Hepatoprotective activity

• Bangladesh
• Chemical and Drug Induced Liver Injury/drug therapy
• Chemical and Drug Induced Liver Injury/metabolism
• Ethnopharmacology/methods
• Ethnopharmacology/trends
• Humans
• Phytochemicals/pharmacology
• Protective Agents/pharmacology

Previous studies have shown that naringenin (Nar) can play a protective role in animal models with acute liver injury, but its role in alcoholic liver disease (ALD) remains unclear.

To explore the effect of Nar on ALD rats and the possible mechanism involved.

Forty Sprague-Dawley rats were randomly divided into a control group, model group, low-dose Nar group, and high-dose Nar group, with 10 rats in each group. A rat model of ALD was generated by alcohol induction. Blood samples and liver tissues were collected at the end of the regimen. The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum were determined with an automatic biochemical analyzer. The morphology of the liver was observed by HE staining. Glutathione peroxidase (GPX) and superoxide dismutase (SOD) activities, malondialdehyde (MDA) content, and reactive oxygen species (ROS) production level in the liver were determined with commercial kits. The levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in liver tissues were detected by immunohistochemical staining. The expression levels of Nrf-2, HO-1, and p-NF-κB P65 in liver tissues were detected by Western blot.

Compared with the model group, the levels of AST and AST in serum of rats in the low- and high-dose Nar groups were significantly decreased, the activities of SOD and GPx and the expression levels of Nrf-2 and HO-1 in liver tissue were significantly increased, and MDA content, ROS level, and TNF-α, IL-6, and p-NF-κB P65 expression levels were significantly decreased, especially in the high-dose group.

Nar can alleviate liver injury in ALD rats, and this effect may be related to the reduction of oxidative stress and inflammatory response in liver tissue.

• Naringenin
• Alcoholic liver disease
• Anti-oxidant
• Anti-inflammatory

• APAP
• apoptosis
• flavonoids
• hepatic
• oxidative stress

• Acetaminophen/toxicity
• Animals
• Anti-Inflammatory Agents/pharmacology
• Antioxidants/pharmacology
• Apoptosis/drug effects
• Chemical and Drug Induced Liver Injury/etiology
• Chemical and Drug Induced Liver Injury/prevention & control
• Kaempferols/pharmacology
• Male
• Rats
• Rats, Wistar
• Reactive Oxygen Species/metabolism
• Sirtuin 1/metabolism
• Superoxide Dismutase/metabolism
• Up-Regulation/drug effects

• chemical toxins
• naringenin
• natural toxins
• protective effects

The polysaccharides from Grifola frondosa fruiting body can be used as a potential hepatoprotective agent in the treatment of acute liver injury.

Liver diseases and related complications are major sources of morbidity and mortality, which places a huge financial burden on patients and lead to nonnegligible social problems. Therefore, the discovery of novel therapeutic drugs for the treatment of liver diseases is urgently required. Aurantii Fructus Immaturus (AFI) and Aurantii Fructus (AF) are frequently used herbal medicines in traditional Chinese medicine (TCM) formulas for the treatment of diverse ailments. A variety of bioactive ingredients have been isolated and identified from AFI and AF, including alkaloids, flavonoids, coumarins and volatile oils.

Emerging evidence suggests that flavonoids, especially hesperidin (HD), naringenin (NIN), nobiletin (NOB), naringin (NRG), tangeretin (TN), hesperetin (HT) and eriodictyol (ED) are major representative bioactive ingredients that alleviate diseases through multi-targeting mechanisms, including anti-oxidative stress, anti-cytotoxicity, anti-inflammation, anti-fibrosis and anti-tumor mechanisms. In the current review, we summarize the recent progress in the research of hepatoprotective effects of HD, NIN, NOB, NRG, TN, HT and ED and highlight the potential underlying molecular mechanisms. We also point out the limitations of the current studies and shed light on further in-depth pharmacological and pharmacokinetic studies of these bioactive flavonoids.

This review outlines the recent advances in the literature and highlights the potential of these flavonoids isolated from AFI and AF as therapeutic agents for the treatment of liver diseases. Further pharmacological studies will accelerate the development of natural products in AFI and AF and their derivatives as medicines with tantalizing prospects in the clinical application.

• Aurantii Fructus
• Aurantii Fructus Immaturus
• Flavonoids
• Hesperidin
• Liver diseases
• Naringenin

Alcoholic liver disease greatly affects human health. Previous studies have identified that microRNAs (miRNAs) are associated with the pathogenesis of alcoholic liver fibrosis (ALF). Therefore, the present study explored the regulatory mechanism of miR-148a-3p in ALF. An ALF model was established in rats by alcohol gavage, followed by treatment with miR-148a-3p. Reverse transcription-quantitative (RT-q) PCR was performed to detect miR-148a-3p expression in the rat liver tissues. The levels of lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) were determined by enzyme-labeled colorimetry. Liver damage was evaluated by liver indices and histology. The direct target gene of miR-148a-3p was predicted by a dual luciferase reporter assay. The effects of miR-148a-3p and miR-148a-3p in combination with receptor tyrosine-protein kinase erbB-3 (ERBB3) on HSC-T6 cell viability and apoptosis were detected by MTT and flow cytometry assays, respectively. Western blotting and RT-qPCR assays were performed to detect the expression levels of proteins and mRNA associated with fibrosis and apoptosis. The data showed that miR-148a-3p mimics inhibited the expression levels of AST, ALT, ALP, LDH, α-SMA and type I collagen in the model, decreased the liver indices, and improved the liver damage caused by alcohol. ERBB3, which was predicted as the direct target gene of miR-148a-3p, reversed the effects of ERBB3 on promoting cell viability and inhibiting apoptosis. Concomitantly, miR-148a-3p reversed the increased expression of Bcl-2 and inhibited the expression levels of Bax and c-cleaved-3 caused by ERBB3. These data suggested that miR-148a-3p regulated ALF and the viability and apoptosis of hepatic stellate cells through targeting ERBB3.

• Ihh
• Naringin
• PTHrP
• Thiram
• Tibial dyschondroplasia (TD)

• Animals
• Chickens
• Flavanones
• Osteochondrodysplasias
• Poultry Diseases
• Thiram
• Tibia

• gestational diabetes mellitus
• inflammation
• insulin resistance
• naringenin
• oxidative stress

The blueberry is a common fruit that is rich in nutritional value and polyphenol substances. In this study, the blueberry polyphenol content in extract was analysed by spectrophotometry. The results showed that the blueberry polyphenol content in the extract reached 52.7%. A mouse model of liver injury induced by carbon tetrachloride (CCl₄) was established to study the preventive effect of blueberry extract (BE) on liver injury in mice and the experimental animals were examined using biochemical and molecular biological methods. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are important clinical liver function indicators; the changes of triglyceride (TG) and total cholesterol (TC) are observed after liver injury; interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) are important inflammatory indexes; superoxide dismutase (SOD) activity and thiobarbituric acid reactive substances (TBARS) are important changes of oxidative stress indexes. The in vivo animal experiment results showed that BE decreased the liver index of mice with liver injury, BE could reduce the AST, ALT, TG and TC levels and also could reduce the serum cytokine IL-6, TNF-α and IFN-γ levels in mice with liver injury. Moreover, BE increased the SOD activity and decreased the TBARS level in the gastric tissues of mice with liver injury. After treatment with the highest concentration of BP in liver injury mice, these levels returned close to those obtained after treatment with the standard drug of silymarin. Detection of messenger RNA (mRNA) in liver tissue showed that BE upregulated the Cu/Zn-SOD, Mn-SOD and chloramphenicol acetyltransferase (CAT) expression levels and downregulated cyclooxygenase (COX)-2 expression. The effect of BE on mice with liver injury was positively correlated with the BE concentration and was similar to that of silymarin, which is a drug for liver injury, suggesting that BE had a good preventive effect on liver injury. Thus, BE rich in polyphenols is a bioactive substance with value for development and utilization.

• blueberry
• carbon tetrachloride
• liver injury
• mice
• polyphenol

Acetaminophen (APAP), which is also known as paracetamol or N-acetyl-p-aminophenol is a safe and potent drug for fever, pain and inflammation when used at its normal therapeutic doses. It is available as over-the-counter drug and used by all the age groups. The overdose results in acute liver failure that often requires liver transplantation. Current clinical therapy for APAP-induced liver toxicity is the administration of N-acetyl-cysteine (NAC), a sulphydryl compound an approved drug which acts by replenishing cellular glutathione (GSH) stores in the liver. Over the past five decades, several studies indicate that the safety and efficacy of herbal extracts or plant derived compounds that are used either as monotherapy or as an adjunct therapy along with conventional medicines for hepatotoxicity have shown favorable responses. Phytochemicals mitigate necrotic cell death and protect against APAP-induced liver toxicityby restoring cellular antioxidant defense system, limiting oxidative stress and subsequently protecting mitochondrial dysfunction and inflammation. Recent experimental evidences indicat that these phytochemicals also regulate differential gene expression to modulate various cellular pathways that are implicated in cellular protection. Therefore, in this review, we highlight the role of the phytochemicals, which are shown to be efficacious in clinically relevant APAP-induced hepatotoxicity experimental models. In this review, we have made comprehensive attempt to delineate the molecular mechanism and the cellular targets that are modulated by the phytochemicals to mediate the cytoprotective effect against APAP-induced hepatotoxicity. In this review, we have also defined the challenges and scope of phytochemicals to be developed as drugs to target APAP-induced hepatotoxicity.

• APAP
• acetaminophen
• animals
• hepatotoxicity
• hpatoprotection
• natural products
• paracetamol
• phytochemicals
• plants
• preclinical studies
• small molecules

• Acetaminophen/toxicity
• Animals
• Chemical and Drug Induced Liver Injury/drug therapy
• Chemical and Drug Induced Liver Injury/metabolism
• Glutathione/metabolism
• Humans
• Liver/drug effects
• Liver/metabolism
• Oxidative Stress/drug effects
• Phytochemicals/therapeutic use

This study intended to investigate the therapeutic effect of ethanolic extract of Tylophora villosa leaves (E2TL) against paracetamol (PC)-induced hepatotoxicity (PCIH) in mice (Mus musculus). PCIH were generated using daily 250 mg/kg body weight (bw) PC administration by gavage for seven days, and then daily 27.5; 55.0; 82.5; 110.0; or 220.0 mg/kg bw E2TL were treated by gavage for seven or fourteen days. Meanwhile, the controls were given solvent only in the same manner. Mortality, blood glucose, and condition (color, weight, volume) of the livers were observed on day 15 (D15). Serum glutamate pyruvate transaminase (SGPT) and serum glutamate oxaloacetate transaminase (SG0T) were examined on D15, D22, and D30, and then malondialdehyde (MDA) was determined on D15. Results of this study revealed that on D15, the dosage of 110.0 mg/kg bw E2TL most effectively decreased MDA due to PCIH, from 6.78 ± 1.70 μmol/L to 3.45 ± 0.43 μmol/L, approaching the control condition (2.45 ± 0.05 μmol/L). PC administration was really toxic dosage and caused 13.3 % mortality. Blood glucose, weight, and volume of the liver decreased as the effect of PC administration, and then 220.0 mg/kg bw E2TL treatment could recover the condition as well as the controls. Color of the liver indicated a similar recovery by E2TL treatment. SGPT and SG0T increased significantly by PC administration, and this PCIH facts could be recovered gradually near the controls according to the dosages (55.0; 110.0; or 220.0 mg/kg bw) and duration (seven or fourteen days) of E2TL treatment. It could be concluded that E2TL showed therapeutic effect against PCIH in M. musculus.

• M. musculus
• Paracetamol-induced hepatotoxicity
• Therapeutic effects
• Tylophoravillosa

Acetaminophen (paracetamol or APAP) is an analgesic and antipyretic drug that can induce oxidative stress-mediated hepatotoxicity at high doses. Several studies reported that antioxidant nutraceuticals, in particular phenolic phytochemicals from dietary food, spices, herbs and algae have hepatoprotective effects. Others, however, suggested that they may negatively impact the metabolism, efficacy and toxicity of APAP. The aim of this review is to discuss the pros and consofthe association of antioxidant nutraceuticals and APAP by reviewing the in vivo evidence, with particular reference to APAP pharmacokinetics and hepatotoxicity. Results from the murine models of APAP-induced hepatotoxicity showed amelioration of liver damage with nutraceuticals coadministration, as well as reductions in tissue markers of oxidative stress, and serum levels of hepatic enzymes, bilirubin, cholesterol, triglycerides and inflammatory cytokines. On the other hand, both increased and decreased APAP plasma levels have been reported, depending on the nutraceutical type and route of administration. For example, studies showed that repeated administration of flavonoids causes down-regulation of cytochrome P450 enzymes and up-regulation of uridine diphosphate glucuronosyltransferases (UGT). Moreover, nutraceuticals can alter the levels of APAP metabolites, such as mercapturate glucuronide, sulfate and cysteine conjugates. Overall, the reviewed in vivo studies indicate that interactions between APAP and nutraceuticals or plant foods exist. However, the majority of data come from animal models with doses of phytochemicals far from dietary ones. Human studies should investigate gene-diet interactions, as well as ethnic variability in order to clarify the pros and cons of co-administering antioxidant nutraceuticals and APAP.

• Acetaminophen
• Antioxidants
• Food-drug interaction
• Nutraceuticals
• Paracetamol

• folic acid
• hyperproliferation
• ornithine decarboxylase
• oxidant-antioxidant defense system
• proliferating cell nuclear antigen
• skin cancer

To explore the protective effects and mechanisms of naringenin (NRG) on hepatic injury induced by isoniazid (INH) and rifampicin (RIF).

Male mice were randomly divided into four groups and treated for 14 d as follows: normal control group was administered intragastrically with normal saline solution alone; model group was administered intragastrically with INH (100 mg/kg) and RIF (100 mg/kg); low- and high-dosage NRG pretreatment groups were administered intragastrically with different doses of NRG (50 or 100 mg/kg) 2 h before INH and RIF challenge. Mice were killed 16 h after the last dose of drug treatment to determine activity of serum transaminases. Oxidative stress was evaluated by measuring hepatic glutathione (GSH) and superoxide dismutase (SOD) and malondialdehyde (MDA) levels. Histopathological changes in hepatic tissue were observed under the optical microscope. Hepatocyte apoptosis was measured by TUNEL assay and caspase-3 activation. Expression of Bcl-2 and Bax in liver was determined by western blot.

Both low- and high-dosage NRG pretreatment obviously alleviated serum levels of alanine aminotransferase and aspartate aminotransferase, liver index, hepatic MDA content, and increased hepatic GSH content and SOD activity compared with the INH and RIF-treated group (44.71 ± 8.15 U/L, 38.22 ± 6.64 U/L vs 58.15 ± 10.54 U/L; 98.36 ± 14.78 U/L, 92.41 ± 13.59 U/L vs 133.05 ± 19.36 U/L; 5.34% ± 0.26%, 4.93% ± 0.25% vs 5.71% ± 0.28%; 2.76 ± 0.67 nmol/mgprot, 2.64 ± 0.64 nmol/mgprot vs 4.49 ± 1.12 nmol/mgprot; 5.91 ± 1.31 mg/gprot, 6.42 ± 1.42 mg/gprot vs 3.11 ± 0.73 mg/gprot; 137.31 ± 24.62 U/mgprot, 148.83 ± 26.75 U/mgprot vs 102.34 ± 19.22 U/mgprot; all P < 0.01 or 0.05). Histopathological evaluation showed obvious necrosis and inflammatory cell infiltration in liver of mice administered INH and RIF; however, mice pretreated with NRG showed minor hepatic injury. In addition, INH and RIF resulted in hepatocyte apoptosis, and NRG pretreatment dramatically suppressed INH- and RIF-induced hepatocytes apoptosis. Furthermore, NRG-mediated anti-apoptotic effects seemed to be in connection with its regulation of Bax and Bcl-2 protein expression in hepatic tissue.

NRG might attenuate INH- and RIF-induced hepatic injury via suppression of oxidative stress and hepatocyte apoptosis.

• Naringenin
• Isoniazid
• Rifampicin
• Oxidative stress
• Apoptosis
• Hepatic injury

• Alanine Transaminase/blood
• Animals
• Antioxidants/pharmacology
• Apoptosis/drug effects
• Aspartate Aminotransferases/blood
• Biomarkers/blood
• Caspase 3/metabolism
• Chemical and Drug Induced Liver Injury/blood
• Chemical and Drug Induced Liver Injury/etiology
• Chemical and Drug Induced Liver Injury/pathology
• Chemical and Drug Induced Liver Injury/prevention & control
• Cytoprotection
• Disease Models, Animal
• Flavanones/pharmacology
• Glutathione/metabolism
• Isoniazid
• Liver/drug effects
• Liver/metabolism
• Liver/pathology
• Male
• Malondialdehyde/metabolism
• Mice, Inbred BALB C
• Oxidative Stress/drug effects
• Proto-Oncogene Proteins c-bcl-2/metabolism
• Rifampin
• Superoxide Dismutase/metabolism
• bcl-2-Associated X Protein/metabolism

Polychlorinated biphenyls (PCBs), industrial chemicals and persistent environmental pollutants, are found in rural and urban settings. Rodent studies have shown that exposure to PCB126, a dioxin-like PCB, causes a significant disruption of hepatic micronutrient homeostasis and an increase in metallothionein (MT), an antioxidant protein and metal carrier. A MT knockout mouse strain was used to assess metallothionein’s role in micronutrient disruption and overall hepatotoxicity. Twenty four 129S male mice (12 wild type (WT) and 12 MT knockout (MTKO)) were placed on a purified diet (AIN-93G) for 3 weeks to achieve hepatic metal equilibrium. Mice were then given a single IP injection of either vehicle or 150 μmol/kg PCB126 in vehicle. The animals were sacrificed 2 weeks later and organs processed for analysis. Liver histology, hepatic lipids, gene expression, micronutrient and ROS status were investigated. Liver weights, liver lipids, ROS, and hepatocyte vacuolation were increased with PCB126 exposure along with AhR responsive genes. The MTKO animals had more severe histological changes in the liver and elevated liver lipids than their wild type counterparts. Hepatic and renal metals levels (Cu, Zn, Se and Mn) were mostly reduced by PCB126 treatment. Renal micronutrients were more affected by PCB126 treatment in the MTKO animals. This research suggests that MT may not be the sole/primary cause of the metal disruption caused by PCB126 exposure in mice, but may provide protection against overall hepatotoxicity.

• AhR
• Metallothionein
• Metals
• Micronutrients
• PCB
• hepatotoxicity

Background Aim. In case of high-dose acetaminophen intake, the active metabolite can not bind to the glutathione, thereby inducing cellular necrosis through binding to the cytosol proteins. This trial was performed to histologically and biochemically investigate whether leptin was protective against liver damage induced by paracetamol at toxic doses. Material and Method. In our trial, 30 female rats, divided into 5 groups, were used. IP leptin administration was performed after an hour in the group of rats, in which paracetamol poisoning was induced. The groups were as follows: Group 1: the control group, Group 2: 20 µg/kg leptin, Group 3: 2 g/kg paracetamol, Group 4: 2 g/kg paracetamol + 10 µg/kg leptin, and Group 5: 2 g/kg paracetamol + 20 µg/kg leptin. Results. The most significant increase was observed in the PARA 2 g/kg group, while the best improvement among the treatment groups occurred in the PARA 2 g/kg + LEP 10 µg/kg group (p < 0.05). While the most significant glutathione (GSH) reduction was observed in the PARA 2 g/kg group, the best improvement was in the PARA 2 g/kg + LEP 10 µg/kg group (p < 0.05). Conclusion. Liver damage occurring upon paracetamol poisoning manifests with hepatocyte breakdown occurring as a result of inflammation and oxidative stress. Leptin can prevent this damage thanks to its antioxidant and anti-inflammatory efficacy.

• Chemopreventive
• Hepatic fibrosis
• Hepatic steatosis
• Hepatoprotection
• Liver inflammation
• Phytochemicals

Treatments for leukemia remain unsatisfactory. Conventional chemotherapy agents that aim to kill tumor cells may also damage normal cells and thus result in severe side-effects. Naringenin, a natural polyphenolic compound with antioxidant effects, has been revealed to have significant antitumor effects with low toxicity in preliminary studies. Thus, it is considered as one of the most promising flavonoids in the treatment of leukemia. In the present study, the effects of naringenin on the K562 human leukemia cell line and the underlying mechanisms were explored in vitro. In addition, human peripheral blood polymorphonuclear leukocytes (PMNs) were used as a normal control in order to evaluate the effects of naringenin on normal granulocytes and in the mediation of Adriamycin (ADM)-induced oxidative damage. The results revealed that K562 proliferation was significantly inhibited by naringenin in a time- and concentration-dependent manner; however, minimal cytotoxic effects were observed in PMNs when naringenin was used at concentrations <400 μmol/l. Morphological changes indicative of apoptosis were observed in naringenin-treated K562 cells. Flow cytometric analysis indicated that the K562 cells were arrested in the G₀/G₁ phase of the cell cycle with a significantly upregulated rate of apoptosis. Furthermore, in the naringenin-treated K562 cells, the labeling index of proliferating cell nuclear antigen was observed to be increased by immunochemical staining, the mRNA and protein expression levels of p21/WAF1 were strongly upregulated in reverse transcription-polymerase chain reaction and western blot analyses, whereas p53 gene expression was not significantly changed. In PMNs to which naringenin (50~80 μmol/l) was added 1 h subsequent to ADM, the cell damage induced by ADM was significantly reduced, coincident with reductions in the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and increases in the activity of superoxide dismutase and glutathione peroxidase. However, the cytotoxic effect of ADM in K562 cells was not significantly altered by naringenin, and the oxidative stress indices in K562 cells remained stable. In conclusion, the present study revealed the promising value of naringenin in leukemia treatment. Naringenin demonstrated a significant inhibitory effect on the growth of K562 cells but not on normal PMNs. Furthermore, naringenin protected PMNs from ADM-induced oxidative damage at low concentrations. Cell cycle arrest and apoptosis-inducing effects, achieved through p53-independent p21/WAF1 upregulation, are likely to be the mechanism of the antileukemic effects of naringenin, and the protective effect against ADM chemotherapy-induced damage in PMNs may be due to the antioxidant capability of this agent at low concentrations.

• K562
• apoptosis
• cell cycle
• cell line
• gene
• naringenin
• p21
• p53