The global prevalence of diabetes mellitus (DM) and its complications has been showing an upward trend in the past few decades, posing an increased economic burden to society and a serious threat to human life and health. Therefore, it is urgent to investigate the effectiveness of complementary and alternative therapies for DM and its complications. Luteolin is a kind of polyphenol flavonoid with widely existence in some natural resources, as a safe dietary supplement, it has been widely studied and reported in the treatment of DM and its complications. This review demonstrates the therapeutic potential of luteolin in DM and its complications, and elucidates the action mode of luteolin at the molecular level. It is characterized by anti-inflammatory, antioxidant, and neuroprotective effects. In detail, luteolin can not only improve endothelial function, insulin resistance and β-cell dysfunction, but also inhibit the activities of dipeptidyl peptidase-4 and α-glucosidase. However, due to the low water solubility and oral bioavailability of luteolin, its application in the medical field is limited. Therefore, great importance should be attached to the joint application of luteolin with current advanced science and technology. And more high-quality human clinical studies are needed to clarify the effects of luteolin on DM patients.
Humans ; Luteolin/pharmacology* ; Diabetes Mellitus/drug therapy* ; Diabetes Complications/drug therapy* ; Animals ; Antioxidants/therapeutic use*

OBJECTIVES: To investigate the mechanism of luteolin for inhibiting proliferation of lung cancer A549 cells. METHODS: A549 cells treated with different concentrations of luteolin for 48 h were evaluated for changes in cell viability, proliferation, reactive oxygen species (ROS) production and apoptosis using MTT assay, plate cloning assay, EdU staining, DCFH-DA assay and Hoechst33258 staining. The changes in cell autophagy were examined with MDC staining, and the expressions of apoptosis-related proteins (Bax, Bcl-2, and cleaved caspase-9), autophagy-related proteins (LC3B, Beclin 1, and P62), AKT/mTOR pathway proteins, and HO-1 protein were detected using Western blotting. RESULTS: Treatment with luteolin dose-dependently inhibited the viability and proliferation of A549 cells, increased intracellular ROS levels, up-regulated the expressions of Bax, cleaved caspase-9, and Beclin 1, increased the LC3B-II/LC3B-I ratio, down-regulated the expressions of Bcl-2 and P62, and induced cell apoptosis and autophagy. Luteolin also significantly inhibited the phosphorylation of AKT and mTOR and down-regulated the expression of HO-1 protein in the cells. CONCLUSIONS Luteolin induces apoptosis and autophagy to inhibit proliferation of A549 cells by increasing ROS production, inhibiting the AKT/mTOR pathway and down-regulating HO-1 protein expression.
Humans ; TOR Serine-Threonine Kinases/metabolism* ; A549 Cells ; Reactive Oxygen Species/metabolism* ; Proto-Oncogene Proteins c-akt/metabolism* ; Cell Proliferation/drug effects* ; Signal Transduction/drug effects* ; Lung Neoplasms/pathology* ; Apoptosis/drug effects* ; Luteolin/pharmacology* ; Autophagy/drug effects* ; Heme Oxygenase-1/metabolism* ; Cell Survival/drug effects*

OBJECTIVE: Myocardial ischemia/reperfusion injury (MIRI) is an obstacle to the success of cardiac reperfusion therapy. This study explores whether luteolin can mitigate MIRI by regulating the p53 signaling pathway. METHODS: Model mice were subjected to a temporary surgical ligation of the left anterior descending coronary artery, and administered luteolin. The myocardial infarct size, myocardial enzyme levels, and cardiac function were measured. Latent targets and signaling pathways were screened using network pharmacology and molecular docking. Then, proteins related to the p53 signaling pathway, apoptosis and oxidative stress were measured. Hypoxia/reoxygenation (HR)-incubated HL1 cells were used to validate the effects of luteolin in vitro. In addition, a p53 agonist and an inhibitor were used to investigate the mechanism. RESULTS: Luteolin reduced the myocardial infarcted size and myocardial enzymes, and restored cardiac function in MIRI mice. Network pharmacology identified p53 as a hub target. The bioinformatic analyses showed that luteolin had anti-apoptotic and anti-oxidative properties. Additionally, luteolin halted the activation of p53, and prevented both apoptosis and oxidative stress in myocardial tissue in vivo. Furthermore, luteolin inhibited cell apoptosis, JC-1 monomer formation, and reactive oxygen species elevation in HR-incubated HL1 cells in vitro. Finally, the p53 agonist NSC319726 downregulated the protective attributes of luteolin in the MIRI mouse model, and both luteolin and the p53 inhibitor pifithrin-α demonstrated a similar therapeutic effect in the MIRI mice. CONCLUSION Luteolin effectively treats MIRI and may ameliorate myocardial damage by regulating apoptosis and oxidative stress through its targeting of the p53 signaling pathway. Please cite this article as: Zhai P, Ouyang XH, Yang ML, Lin L, Li JY, Li YM, Cheng X, Zhu R, Hu DS. Luteolin protects against myocardial ischemia/reperfusion injury by reducing oxidative stress and apoptosis through the p53 pathway. J Integr Med. 2024; 22(6): 652-664.
Luteolin/pharmacology* ; Animals ; Myocardial Reperfusion Injury/metabolism* ; Oxidative Stress/drug effects* ; Tumor Suppressor Protein p53/genetics* ; Apoptosis/drug effects* ; Mice ; Signal Transduction/drug effects* ; Male ; Disease Models, Animal ; Mice, Inbred C57BL ; Myocardial Infarction/prevention & control* ; Reactive Oxygen Species/metabolism*

OBJECTIVE: To screen the effective antioxidant components in Trichosanthes extract based on the mean value of Deng's correlation degree and assess the antioxidant activity of the identified components. METHOD: High-performance liquid chromatography (HPLC) was used to obtain the fingerprints of Trichosanthes extract, and the clearance rates of DPPH · and O₂^-· by 3, 9 and 27 mg/mL Trichosanthes extract were determined. The antioxidant spectrum effect of Trichosanthes extract was analyzed by calculating the mean value of Deng's correlation degree to screen the effective antioxidant component group. According to the contents of each known components in the antioxidant effective component group, mixed solutions of the components were prepared and tested for their clearance rates of DPPH · and O₂^-·. RESULTS: The 36 common peaks in HPLC fingerprints of Trichosanthes extract showed different degrees of correlation with DPPH · and O₂^-· clearance. The common peaks with a correlation degree greater than the median value included peaks 21, 36, 8, 31, 14, 5, 27, 2, 24, 15, 18, 33, 22, 34, 35, 19, 28 and 25. The 5 components, namely kaempferol (peak 36), isoquercitrin (peak 8), luteolin (peak 31), rutin (peak 5) and apigenin (peak 35), were tentatively identified to constitute the effective antioxidant component group with a mass ratio 3∶2∶2∶ 1∶1 in Trichosanthes extract. The prepared mixed solutions of antioxidant effective component group (6.12, 2.04, and 0.68 μg/mL) showed clearance rates of DPPH · of 65.4%, 64.0% and 61.0%, and clearance rates of O₂^-· of 12.9%, 9.5% and 8.3%, respectively. CONCLUSION We identified the material basis for the antioxidant activity of Trichosanthes and screened the antioxidant effective component group in Trichosanthes extract.
Antioxidants/pharmacology* ; Chromatography, High Pressure Liquid/methods* ; Luteolin ; Plant Extracts/pharmacology* ; Trichosanthes/chemistry*

The aim of this study was to investigate the mechanism of luteolin regulating lipoxygenase pathway against oxygen-glucose deprivation/reperfusion(OGD/R) injury in H9 c2 cardiomyocytes. First, Discovery Studio 2019 was used for the molecular docking of luteolin with three key enzymes including lipoxygenase 5(ALOX5), lipoxygenase 12(ALOX12), and lipoxygenase 15(ALOX15) in lipoxygenase pathway. The docking results showed that luteolin had high docking score and similar functional groups with the original ligand. From this, H9 c2 cardiomyocytes were cultured in vitro, and then the injury model of H9 c2 cardiomyocytes was induced by deprivation of oxygen-glucose for 8 h, and rehabilitation of oxygen-glucose for 12 h. Cell viability was detected by tetrazolium(MTT) colorimetry. H9 c2 cardiomyocytes were observed with a fluorescence inverted microscope, and colorimetry was used to detect the level of lactate dehydrogenase(LDH) in cell supernatant. The results showed that luteolin could significantly protect the morphology of H9 c2 cells, significantly improve the survival rate of H9 c2 cardiomyocytes in OGD/R injury model, reduce the level of LDH in cell supernatant, inhibit cytotoxicity, and maintain the integrity of cell membrane. The inflammatory cytokines interleukin-6(IL-6) and tumor necrosis factor-α(TNF-α) were detected by enzyme-linked immunosorbent assay. Compared with the model group, luteolin can significantly reduce the release of IL-6 and TNF-α. Western blot was employed to detect the protein levels of ALOX5, ALOX12, and ALOX15 in lipoxygenase pathway. After luteolin intervention, the protein levels of ALOX5, ALOX12, and ALOX15 were significantly down-regulated compared with those in model group. These results indicate that luteolin can inhibit the release of IL-6 and TNF-α by restraining the activation of lipoxygenase pathway, thereby playing a protective role in the cardiomyocyte injury model induced by OGD/R.
Apoptosis ; Glucose ; Humans ; Lipoxygenases ; Luteolin/pharmacology* ; Molecular Docking Simulation ; Myocytes, Cardiac ; Oxygen ; Reperfusion Injury ; Signal Transduction

Objective: This study aimed to investigate the effect of exposure to a 900 MHz electromagnetic field (EMF) on the cervical spinal cord (CSC) of rats and the possible protective effect of luteolin (LUT) against CSC tissue damage. Methods: Quantitative data were obtained stereological, biochemical, immunohistochemical, and histopathological techniques. We investigated morphometric value, superoxide dismutase (SOD) level, and the expression of high-mobility group box 1 protein molecules, as well as histological changes. Results: The total number of motor neurons in the EMF group significantly decreased in comparison with that in the control group ( < 0.05). In the EMF + LUT group, we found a significant increase in the total number of motor neurons compared with that in the EMF group ( < 0.05). SOD enzyme activity in the EMF group significantly increased in comparison with that in the control group ( < 0.05). By contrast, the EMF+LUT group exhibited a decrease in SOD level compared with the EMF group ( < 0.05). Conclusion Our results suggested that exposure to EMF could be deleterious to CSC tissues. Furthermore, the protective efficacy of LUT against SC damage might have resulted from the alleviation of oxidative stress caused by EMF.
Animals ; Antioxidants ; pharmacology ; Electromagnetic Fields ; adverse effects ; Luteolin ; pharmacology ; Male ; Rats ; Rats, Wistar ; Spinal Cord ; drug effects ; radiation effects

The purpose of the present study was to investigate the effect of luteolin on the angiogenesis and invasion of breast cancer cells. MTT assay was used to examine breast cancer proliferation. The chick chorioallantoic membrane model was used to assess the angiogenesis effect. Wound healing assay was used to assess cell invasion ability. Western blot was used to analyze Bcl-2, AEG-1 and MMP-2 expression levels. The results showed luteolin inhibited MCF-7 cells proliferation in a dose- and time-dependent manner, and the expression of Bcl-2 protein was decreased. Luteolin had a strong anti-angiogenesis of chick chorioallantoic membrane. After treatment of MCF-7 cells with luteolin at 60 μmol/L for 48 h, migration rate was reduced by 71.07% compared with control (P < 0.01). After treatment of MCF-7 cells with luteolin at 60 μmol/L for 48 h, the expression of AEG-1 and MMP-2 was reduced by 82.34% (P < 0.05) and 85.70% (P < 0.05) respectively, compared with control. In conclusion, the results suggest that luteolin can inhibit the proliferation of breast cancer cells, and suppress the expression of Bcl-2. Furthermore, luteolin has strong anti-angiogenesis of chick chorioallantoic membrane and anti-invasive activity on breast cancer cells, and down-regulates the expression of AEG-1 and MMP-2.
Animals ; Breast Neoplasms ; pathology ; Cell Adhesion Molecules ; metabolism ; Cell Proliferation ; Chickens ; Chorioallantoic Membrane ; drug effects ; Down-Regulation ; Female ; Humans ; Luteolin ; pharmacology ; MCF-7 Cells ; Matrix Metalloproteinase 2 ; metabolism ; Neovascularization, Pathologic ; pathology ; Proto-Oncogene Proteins c-bcl-2 ; metabolism

OBJECTIVETo investigate the effect of luteolin on cell growth and apoptosis of HepG2 cells in vitro.

METHODSCultured HepG2,HL60,A549 and LO2 cells were treated with luteolin for different doses (0 μg/ml,2.5 μg/ml,10 μg/ml and 20 μg/ml) and varied times (0 h,24 h,48 h and 72 h). Cell viability was measured with MTT assay and IC50 was calculated. The reactive oxygen species (ROS) levels in HepG2 cells treated with luteolin for 6 h and 12 h were measured with flow cytometry. Cell apoptosis of HepG2 cells treated with luteolin for 24h was examined with flow cytometry and Annexin V-FITC/PI. Expression levels of apoptosis pathway proteins (p53,ASPP2 and iASPP) in HepG2 cells were detected with western blot and the dose and time-effect was analyzed.

RESULTSLuteolin effectively inhibited tumor cell proliferation in a dose-and time-dependent manner,and the inhibition rates of 20 μg/ml Luteolin for 72 h were 39.34%,62.90%,57.57% and 62.90% to LO2,HepG2, HL60 and A549 cells,respectively. The intracellular ROS level was decreased in HepG2 cells by 13.88% and 41.11% after being treated with luteolin for 6 h and 12 h,respectively. The apoptosis rate of HepG2 cells treated with luteolin for 24 h was 14.43%,and western blot showed that luteolin reduced the expression level of iASPP by 77.07% and up-regulated the expression of p53 by 179.37% and ASPP2 by 725.02% in HepG2 cells treated with luteolin for 12 h.

CONCLUSIONLuteolin has ant-proliferative and pro-apoptotic activity on hepatoma HepG2 cells, which is associated with the altered expression of pro-apoptotic factors and decreased ROS level in HepG2 cells.

Apoptosis ; drug effects ; Hep G2 Cells ; Humans ; Luteolin ; administration & dosage ; pharmacology ; Reactive Oxygen Species ; metabolism

OBJECTIVETo investigate the protective effect of luteolin on isolated rat heart in hypothermic preservation.

METHODSForty male SD rats were randomly divided into 4 groups (n = 10): control group, luteolin low-dose group (7.5 micromol/L), middle-dose group (15 micromol/L) and high dose group (30 micromol/L). Langendorff model of isolated rat heart was used. After 30 min basal perfusion, the hearts were stored in University of Wisconsin solution (UW solution) at 4 degrees C with luteolin (7.5, 15 and 30 micromol/L) or without luteolin for 12 h and followed by 60 min reperfusion. The recovery of cardiac contractile and diastolic function, coronary flow (CF), creatine kinase (CK) leakage in the coronary effluent, myocardial water content were determined. The myocardial ultrastructure was also observed.

RESULTSThe results revealed that luteolin improved the recovery of left ventricular peak systolic pressure and +/- dp/dtmax dose-dependently and increased coronary flow. The leakage of creatine kinase in the coronary effluent was significantly reduced in luteolin-added hearts. Impairment of myocardial ultrastructure after 12 h hypothermic preservation was obviously alleviated in hearts luteolin-added group compared with that in control group. There were no differences between the groups in myocardial water contents.

CONCLUSIONLuteolin as a supplementation in cardiac preservation solution can significantly improve the hypothermic preservation effects on rat heart and have myocardial protection effect, especially in luteolin-added with 30 micromol/L.

Animals ; Cryopreservation ; In Vitro Techniques ; Luteolin ; pharmacology ; Male ; Myocardium ; Organ Preservation ; methods ; Organ Preservation Solutions ; Rats

OBJECTIVETo study luteolin-induced non-small cell lung cancer cell line A549 apoptosis and the molecular mechanism for inhibiting its cycle arrest (G2 stage).

METHODMTT assay showed that luteolin had obvious inhibitory effect on A549 and indicated the half inhibition ratio (IC50). Cell cycle and apoptosis were detected by Hoechst 33258 nuclear staining assay, Annexin V-FITC/PI double staining and flow cytometry. Western blotting assay revealed changes in cycle and apoptosis-related proteins induced by luteolin. Possible molecular mechanism was suggested by Western blotting and immunocytochemistry.

RESULTLuteolin had an obvious growth inhibitory effect on A549 cells, with IC50 of 45.2 micromol x L(-1) at 48 h. Flow cytometry showed A549 cells mainly arrested in G2 stage after being treated by luteolin, with low expressions in cyclin A, p-CDC2 and p-Rb. Hoechst 33258 nuclear staining and Annexin V-FITC/PI double staining showed that the luteolin treatment group showed a significant apoptosis rate than the non-treatment group. Western blotting found luteolin can increase phosphorylation of JNK and decrease that of NF-kappaKB (p65). Immunocytochemistry results revealed luteolin can inhibit TNF-alpha-stimulated p65 from nuclear translocation as a transcription factor and thus promoting cell apoptosis.

CONCLUSIONLuteolin can obviously induce apoptosis of human non-small cell lung cancer cell A549 possibly by increasing phosphorylation of JNK to activate mitochondria apoptosis pathway, while inhibiting NF-kappaB from nuclear translocation as a transcription factor.

Annexin A5 ; metabolism ; Apoptosis ; drug effects ; Blotting, Western ; Carcinoma, Non-Small-Cell Lung ; metabolism ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Humans ; Luteolin ; pharmacology ; NF-kappa B ; metabolism