Inhibitory Effect Of Luteolin Research Articles

Inhibitory activity of luteolin on α‐glucosidase and pancreatic lipase in vitro and in vivo

SummaryObesity is becoming a top global health problem. Inhibition of digestive enzymes is an effective approach in weight management due to the reduction of energy absorption. In this study, the inhibitory effects of luteolin on α‐glucosidase and pancreatic lipase were investigated in vitro and in vivo via enzyme kinetics, fluorescence quenching, molecular docking and rat experiments. The results showed that luteolin inhibited α‐glucosidase and pancreatic lipase in a mixed‐type and uncompetitive manner with IC50 values of 29.31 and 42.74 μg mL−1 respectively. The binding of luteolin with the two enzymes caused the quenching of intrinsic fluorescence of protein. Molecular docking simulation revealed that luteolin could be located in the active pocket of α‐glucosidase and interact with the key amino acid residues. Moreover, a hydrophobic interaction and a van der Waals force were formed between luteolin and the key amino acid residues of pancreatic lipase (His264 and Ser153). In vivo studies further confirmed that luteolin could significantly decrease the absorption of glucose and triacylglyceride in rats by inhibiting α‐glucosidase and pancreatic lipase.

A20, as a downstream factor of Nrf2, is involved in the anti-neuroinflammatory and antidepressant-like effects of luteolin

• Luteolin exerted anti-neuroinflammatory and antidepressant-like effects. • Luteolin upregulated the expression of A20 and Nrf2. • Upregulation of A20 and Nrf2 was involved in the inhibitory effects of luteolin on neuroinflammation. • A20, as a downstream factor of Nrf2, was involved in the inhibitory effects of luteolin on activation of microglia. Microglia-mediated neuroinflammation is closely related to depression. Many studies have shown that the NF-κB pathway was involved in the anti-neuroinflammatory effects of luteolin. However, more detailed molecular mechanisms should be further studied. In this study, our data indicated that luteolin inhibited neuroinflammation and alleviated depression-like behavior in a lipopolysaccharide (LPS)-induced mouse model. Further investigation revealed that luteolin increased the expression of A20 and Nrf2 and decreased the expression of TRAF6 while removing K63-linked polyubiquitin chains from TRAF6. Knockdown treatment using siRNA-A20 or Nrf2 reversed the effects of luteolin on neuroinflammation. This study explored the novel mechanism by which luteolin exerted anti-neuroinflammatory and antidepressant-like effects in a lipopolysaccharide-induced mouse model, which might be related to the upregulation of A20 and Nrf2. Notably, A20 exerted its function as a downstream factor of Nrf2. This study provides evidence for the potential application of luteolin in the prevention and treatment of neuroinflammation and depression.

Inhibitory effects of luteolin on TLR3-mediated inflammation caused by TAK/NF-κB signaling in human corneal fibroblasts.

To study the role of luteolin (LUT) in the expression of toll-like receptors 3 (TLR3) ligand polyI:C stimulated inflammatory factors in human corneal fibroblasts (HCFs). HCFs cells were cultivated with or without LUT or polyI:C. The expression levels of interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), vascular cell adhesion molecule (VCAM)-1, as well as intercellular adhesion molecule (ICAM)-1 were measured using enzyme-linked immunosorbent assay (ELISA), immunoblotting or reverse transcription-quantitative polymerase chain reaction (PCR) analyses. Immunoblotting was used to assess toll-interleukin-1 receptor-domain-containing adapter-inducing interferon-β (TRIF), TLR3, transforming growth factor-b-activated kinase 1 (TAK1), tumor necrosis factor receptor-associated factor 6 (TRAF6), the transcription factor AP-1, as well as transcription factor nuclear factor (NF-κB)-inhibitory protein IκB-α degradation and phosphorylation. Immunofluorescence assays were used to localize the cellular location of the p65 subunit of NF-κB. Corneal fibroblasts exposed to polyI:C demonstrated decreased VCAM-1, ICAM-1, MCP-1, IL-6, and IL-8 expression levels upon exposure to LUT in a time-dependent and concentration-dependent manner. LUT was observed to suppress polyI:C-triggered expression of TLR3, the translocation of NF-κB p65 into cell nuclei, as well as the phosphorylation of TAK, c-Jun, and IκB-α, while no impact on the expression levels of TRIF and TRAF6 were observed. LUT suppress the expression of proinflammatory adhesion molecules, chemokines, and cytokines in polyI:C exposed HCFs. These effects are likely mediated through TAK/NF-κB signal attenuation. Therefore, LUT is a candidate molecule that can prevent the TLR3-mediated inflammation response associated with corneal viral infection.

Inhibitory effects of luteolin and its derivatives on osteoclast differentiation and differences in luteolin production by Capsicum annuum varieties.

Luteolin, an abundant flavonoid in the leaves of Capsicum annuum, has antioxidant activity and is, thus, a key chemical for promoting plant residue utilization, especially for the development of healthcare products. We assessed the inhibitory effect of luteolin and its glycosides on osteoclastic differentiation in human cells and found that the differentiation was effectively inhibited at noncytotoxic concentrations. We also screened 47 varieties of C. annuum for the accumulation of luteolin and apigenin to determine the prevalence of luteolin in diverse cultivars and identify varieties with high and/or selective luteolin production. The glycosides of luteolin and apigenin were found in all the tested varieties, with luteolin predominant over apigenin in most varieties. The identification and characterization of highly productive varieties of C. annuum is expected to be beneficial for the effective development of useful luteolin-based products from plant residues.

Luteolin inhibits H2O2-induced cellular senescence via modulation of SIRT1 and p53.

Luteolin, a sort of flavonoid, has been reported to be involved in neuroprotective function via suppression of neuroinflammation. In this study, we investigated the protective effect of luteolin against oxidative stress-induced cellular senescence and its molecular mechanism using hydrogen peroxide (H2O2)-induced cellular senescence model in House Ear Institute-Organ of Corti 1 cells (HEI-OC1). Our results showed that luteolin attenuated senescent phenotypes including alterations of morphology, cell proliferation, senescence-associated β-galactosidase expression, DNA damage, as well as related molecules expression such as p53 and p21 in the oxidant challenged model. Interestingly, we found that luteolin induces expression of sirtuin 1 in dose- and time-dependent manners and it has protective role against H2O2-induced cellular senescence by upregulation of sirtuin 1 (SIRT1). In contrast, the inhibitory effect of luteolin on cellular senescence under oxidative stress was abolished by silencing of SIRT1. This study indicates that luteolin effectively protects against oxidative stress-induced cellular senescence through p53 and SIRT1. These results suggest that luteolin possesses therapeutic potentials against age-related hearing loss that are induced by oxidative stress.

Luteolin ameliorates lipopolysaccharide-induced microcirculatory disturbance through inhibiting leukocyte adhesion in rat mesenteric venules

BackgroundMicrocirculatory disturbance is closely associated with multiple diseases such as ischemic and septic stroke. Luteolin (3,4,5,7-tetrahydroxyflavone) is a vascular protective flavonoid present in several dietary foods. However, how luteolin plays a role in microcirculatory disturbance is still unknown. The purpose of this study was to find out the influence of luteolin on the lipopolysaccharide (LPS)-induced microcirculatory disturbance, focusing on its effect on leukocyte adhesion and the underlying mechanism of this effect.MethodsAfter injecting LPS into rats, we used an inverted intravital microscope to observe the velocity of red blood cells in venules, numbers of leukocytes adherent to and emigrated across the venular wall, hydrogen peroxide production in venular walls and mast cell degranulation. Intestinal microcirculation blood flow was measured by High-resolution Laser Doppler Perfusion Imaging. Histological changes of small intestine and mesenteric arteries were evaluated. Additionally, cell adhesion stimulated by LPS was tested on EA.hy926 and THP-1 cells. The production of pro-inflammatory cytokines, adhesion molecules and the activation of TLR4/Myd88/NF-κB signaling pathway were determined.ResultsThe results showed luteolin significantly inhibited LPS-induced leukocyte adhesion, hydrogen peroxide production and mast cell degranulation, and increased intestinal microcirculation blood flow and ameliorated pathological changes in the mesenteric artery and the small intestine. Furthermore, luteolin inhibited the release of pro-inflammatory cytokines, the expression of TLR4, Myd88, ICAM-1, and VCAM-1, the phosphorylation of IκB-α and NF-κB/p65 in LPS stimulated EA.hy926.ConclusionsOur findings revealed that it is likely that luteolin can ameliorate microcirculatory disturbance. The inhibitory effects of luteolin on the leukocyte adhesion stimulated by LPS, which participates in the development of microcirculatory disturbance, are mediated through the regulation of the TLR4/Myd88/NF-κB signaling pathway.

Inhibitory effect of luteolin on the growth, migration and vasculogenic mimicry formation of a melanoma cell line B16

Objective To evaluate the effect of luteolin on the growth, migration and vasculogenic mimicry formation of a melanoma cell line B16. Methods In vitro cultured B16 melanoma cells were divided into 4 groups: low-, middle- and high-dose luteolin groups treated with 2.5, 5, 10 μmol/L luteolin respectively, and control group treated with 0.1% dimethyl sulfoxide (DMSO) . Scratch assay, Transwell invasion assay and vascular channel formation assay were performed to assess the migration, invasion of and vascular channel formation by melanoma cells. A model of subcutaneous transplanted B16 melanoma was established in 12 C57 mice, which were randomly and equally divided into 4 groups: control group gavaged with ultrapure water, low-, middle- and high-dose luteolin groups gavaged with 10, 20, 40 mg/kg luteolin respectively every day. The above treatment for the tumor-bearing mice lasted till day 28, and then these mice were sacrificed. Meanwhile, the lung and tumor tissues of the mice were excised, and the growth, metastasis and vasculogenic mimicry of transplanted melanoma were observed. Immunofluorescence and immunohistochemical studies were performed to evaluate the effects of luteolin on the expression of vascular endothelial cadherin (VE-cadherin) , vascular endothelial growth factor receptor 1 (VEGFR1) , VEGFR2, matrix metalloproteinase-2 (MMP-2) and MMP-9 in the transplanted melanoma. Means were compared among several groups by using one-way analysis of variation or rank sum test. Results In vitro study showed that the relative scratch width at 48 hours significantly differed among the control group, low-, middle- and high-dose luteolin groups (0.47 ± 0.04, 0.64 ± 0.04, 0.73 ± 0.03, 0.84 ± 0.04 respectively; F=34.51, P < 0.001) , and the migration ability of B16 cells was significantly lower in the low-, middle- and high-dose luteolin groups than in the control group (all P < 0.05) . At 24 hours, there were significant differences in the number of cells crossing the Transwell membrane among the control group, low-, middle- and high-dose luteolin groups (281.00 ± 8.79, 169.00 ± 15.35, 92.00 ± 14.79 and 57.00 ± 13.72 respectively; F=275.30, P < 0.001) , and the invasive ability was significantly lower in the low-, middle- and high-dose luteolin groups than in the control group (P < 0.01) . Meanwhile, the number of formed vascular channels also differed among the above 4 groups (20.00 ± 2.77, 11.00 ± 1.28, 7.00 ± 1.86 and 2.00 ± 1.32 respectively; F=48.61, P < 0.001) , and the number of vascular channels was significantly lower in the low-, middle- and high-dose luteolin groups than in the control group (all P < 0.01) . In vivo study showed that the tumor size significantly differed among the control group, low-, middle- and high-dose luteolin groups (5.10 ± 1.72, 4.02 ± 2.13, 2.98 ± 0.92, 1.49 ± 1.13 cm3 respectively; F=28.76, P < 0.001) , and was significantly lower in the low-, middle- and high-dose luteolin groups than in the control group (t=3.86, 7.11 and 13.06 respectively, all P < 0.01) . CD31-PAS double staining showed that the number of vasculogenic mimicry was significantly higher in the control group than in the low-, middle- and high-dose luteolin groups (all P < 0.01) . In vivo and in vitro studies both showed that the expression of vasculogenic mimicry-related markers in the cells or mouse tumor tissues was significantly lower in the high-dose luteolin group than in the control group (P < 0.05) . Conclusion Luteolin can effectively inhibit the growth, metastasis and vasculogenic mimicry formation of melanoma. Key words: Melanoma, experimental; Luteolin; Neoplasm metastasis; Receptors, vascular endothelial growth factor; Collagenases; Vasculogenic mimicry

Decrease of AIM2 mediated by luteolin contributes to non-small cell lung cancer treatment

Non-small cell lung cancer (NSCLC) is one of the most common malignancies in the world. Although extensive studies showed that luteolin exhibited antitumor effects against NSCLC, the mechanism has not been fully established. In the present study, we found that luteolin significantly reduced the expression of absent in melanoma 2 (AIM2) at both mRNA and protein levels leading to the suppression of AIM2 inflammasome activation, which induced G2/M phase arrest and inhibited epithelial–mesenchymal transition (EMT) in NSCLC. Furthermore, the inhibitory effects of luteolin on NSCLC cells were abolished by the knockdown of AIM2. On the contrary, the antitumor effects of luteolin could be notably reversed by the overexpression of AIM2. In addition, luteolin reduced poly(dA:dT)-induced caspase-1 activation and IL-1β cleavage in NSCLC cells. These findings suggested that AIM2 was essential to luteolin-mediated antitumor effects. The antitumor effects of luteolin, which were closely associated with AIM2, were also confirmed in the A549 and H460 xenograft mouse models. Collectively, our study displayed that the antitumor effects of luteolin on NSCLC were AIM2 dependent and the downregulation of AIM2 might be an effective way for NSCLC treatment.

Lysozyme-luteolin binding: molecular insights into the complexation process and the inhibitory effects of luteolin towards protein modification.

In the proposed work, the complexation of bioactive flavonoid luteolin with hen egg white lysozyme (HEWL) along with its inhibitory influence on HEWL modification has been explored with the help of multi-spectroscopic and computational methods. The binding affinity has been observed to be moderate in nature (in the order of 104 M-1) and the static quenching mechanism was found to be involved in the fluorescence quenching process. The binding constant (Kb) shows a progressive increase with the increase in temperature from (4.075 ± 0.046 × 104 M-1) at 293 K to (6.962 ± 0.024 × 104 M-1) at 313 K under experimental conditions. Spectroscopic measurements along with molecular docking calculations suggest that Trp62 is involved in the binding site of luteolin within the geometry of HEWL. The positive changes in enthalpy (ΔH = +19.99 ± 0.65 kJ mol-1) as well as entropy (ΔS = +156.28 ± 2.00 J K-1 mol-1) are indicative of the presence of hydrophobic forces that stabilize the HEWL-luteolin complex. The micro-environment around the Trp residues showed an increase in hydrophobicity as indicated by synchronous fluorescence (SFS), three dimensional fluorescence (3D) and red edge excitation (REES) studies. The % α-helix of HEWL showed a marked reduction upon binding with luteolin as indicated by circular dichroism (CD) and Fourier-transform infrared spectroscopy (FTIR) studies. Moreover, luteolin is situated at a distance of 4.275 ± 0.004 nm from the binding site as indicated by FRET theory, and the rate of energy transfer kET (0.063 ± 0.004 ns-1) has been observed to be faster than the donor decay rate (1/τD = 0.606 ns-1), which is indicative of the non-radiative energy transfer during complexation. Leaving aside the binding study, luteolin showed promising inhibitory effects towards the d-ribose mediated glycation of HEWL as well as towards HEWL fibrillation as studied by fluorescence emission and imaging studies. Excellent correlation with the experimental observations as well as precise location and dynamics of luteolin within the binding site has been obtained from molecular docking and molecular dynamics simulation studies.

Bioactive luteoloside produced by Myroides odoratimimus, solvent-tolerant bacterium form the rhizosphere of Lonicera japonica

Luteoloside (luteolin-7-O-glucoside), the biomarker of Lonicera japonica, was efficiently bio-synthetized from its cheaper precursor luteolin. The structure of luteoloside was characterized by LC-MS and NMR analyses. Compared to the significant inhibitory effect of luteolin on human hepatocyte cell line LO2 at high doses, luteoloside did not show obvious cytotoxic effects at any test dose. Moreover, luteoloside exhibited obvious promotive effects on human hepatocyte cells, suggesting a potential application in hepatoprotective therapies.

Luteolin inhibits multi-heavy metal mixture-induced HL7702 cell apoptosis through downregulation of ROS-activated mitochondrial pathway.

With the rapid economic development in recent years, China is facing a great challenge due to heavy metal pollution. The heavy metals may enter the human body through ingestion of aqua products to cause great health risks. In the present study, the inhibitory effects of luteolin on the combined toxicity of multi-heavy metals (including zinc, manganese, lead, copper, cadmium, mercury, chromium and nickel) were investigated in HL7702 hepatocyte cells. An MTT assay demonstrated that 20 μM luteolin significantly alleviated the multi-heavy metal mixture-induced cell death and morphological changes. Furthermore, 20 μM luteolin significantly inhibited multi-heavy metal mixture-induced reactive oxygen species (ROS) generation, lipid peroxidation (malondialdehyde content) and caused a decrease in adenosine triphosphate levels in HL7702 cells. A JC-1 staining assay indicated that 20 μM luteolin inhibited the mitochondrial membrane potential-reducing effect of the multi-heavy metal mixture. Apoptotic assays revealed that the multi-heavy metal mixture induced HL7702 cell apoptosis in a dose-dependent manner, which was significantly inhibited by 20 μM luteolin. Western blot analysis indicated that addition of luteolin to the multi-heavy metal mixture significantly alleviated cytochrome c release from the mitochondria into the cytosol. In addition, 20 μM luteolin had a significant inhibitory effect on multi-heavy metal mixture-induced cleavage of caspase-9, caspase-3 and poly(adenosine diphosphate-ribose) polymerase-1 protein. Immunofluorescence staining demonstrated that addition of luteolin significantly alleviated caspase-3 cleavage induced by the multi-heavy metal mixture. The present results suggested luteolin exerts its inhibitory effects of on multi-heavy metal mixture induced cell apoptosis through downregulation of the ROS-activated mitochondrial pathway.

COX-2 inhibitory effect of luteolin through the regulation of NF-κB and ERK in phorbol ester activated human lung epithelial cells

COX-2 inhibitory effect of luteolin through the regulation of NF-κB and ERK in phorbol ester activated human lung epithelial cells

COX-2 inhibitory effect of luteolin through the regulation of NF-κB and ERK in phorbol ester activated human lung epithelial cells

COX-2 inhibitory effect of luteolin through the regulation of NF-κB and ERK in phorbol ester activated human lung epithelial cells

Luteolin Attenuates Airway Mucus Overproduction via Inhibition of the GABAergic System.

Airway mucus overproduction is one of the most common symptoms of asthma that causes severe clinical outcomes in patients. Despite the effectiveness of general asthma therapies, specific treatments that prevent mucus overproduction in asthma patients remain lacking. Recent studies have found that activation of GABAA receptors (GABAAR) is important for promoting mucus oversecretion in lung airway epithelia. Here, we report that luteolin, a natural flavonoid compound, suppresses mucus overproduction by functionally inhibiting the GABAergic system. This hypothesis was investigated by testing the effects of luteolin on goblet cell hyperplasia, excessive mucus secretion, and GABAergic transmission using histological and electrophysiological approaches. Our results showed that 10 mg/kg luteolin significantly decreased the number of goblet cells in the lung tissue and inhibited mucus overproduction in an in vivo asthma model induced by ovalbumin (OVA) in mice. Patch-clamp recordings showed that luteolin inhibited GABAAR-mediated currents in A549 cells. Furthermore, the inhibitory effects of luteolin on OVA-induced goblet cell hyperplasia and mucus overproduction were occluded by the GABAAR antagonist picrotoxin. In conclusion, our observations indicate that luteolin effectively attenuates mucus overproduction at least partially by inhibiting GABAARs, suggesting the potential for therapeutic administration of luteolin in the treatment of mucus overproduction in asthma patients.

Luteolin inhibits recruitment of monocytes and migration of Lewis lung carcinoma cells by suppressing chemokine (C–C motif) ligand 2 expression in tumor-associated macrophage

Tumor-associated macrophages (TAMs) play pivotal roles in the progression of cancer. In order to investigate a novel candidate that inhibits the tumor-supporting M2-like phenotype of TAMs, a murine macrophage cell line RAW 264.7 cells were treated with interleukin (IL)-4. Luteolin inhibited phosphorylation of signal transducer and activator of transcription 6 (STAT6), a main downstream signal of IL-4, and reduced the expression of the M2-associated genes. In addition, Luminex multiplex analysis for secreted cytokines revealed that IL-4–enhanced secretion of chemokine (C–C motif) ligand 2 (CCL2) was reduced by luteolin treatment. IL-4–stimulated migration of monocyte, THP-1 cells, was inhibited by luteolin treatment and recovered by recombinant CCL2 supplement. Moreover, luteolin decreased migration of Lewis lung carcinoma cells in a CCL2–dependent manner. Given the important role of the TAM phenotype in the tumor microenvironment, inhibitory effect of luteolin on the monocyte recruitment and cancer migration via suppression of the TAM-secreted CCL2 may suggest a novel therapeutic approach to treat malignant tumors.

Molecular mechanisms of luteolin induced growth inhibition and apoptosis of human osteosarcoma cells.

Luteolin is a flavone in medicinal plants as well as some vegetables and spices. It is a natural anti-oxidant with less pro-oxidant potential but apparently with a better safety profile. The purpose of this study was to investigate the molecular mechanism of luteolin-mediated apoptosis of MG-63 human osteosarcoma cells. MTT assay kit was employed to evaluate the effects of luteolin on MG-63 cells proliferation. Then, we performed Annexin V-FITC/PI to analyze the apoptotic rate of the cells. Furthermore, the inhibitory effects of luteolin on the expressions of BCL-2, BAX, Caspase-3 and Survivin were detected by Western blotting. As expected, luteolin (0.5, 2.5, 12.5 µg/mL) inhibited the growth of MG-63 cells by inhibiting cell proliferation and inducing cell apoptosis. Western blotting demonstrated that luteolin (0.5, 2.5, 12.5 µg/mL) inhibited the expressions of BCL-2, Caspase-3 and Survivin, and promoted the expression of BAX in MG-63 cells with a concentration dependent way. Luteolin can inhibit osteosarcoma cell proliferation and induce apoptosis effectively in a dose dependent manner through down-regulating the expression of BCL-2, Caspase-3 and Survivin proteins levels and up-regulating the expression of BAX protein level. These findings indicated that luteolin may be used as a novel herbal medicine for the treatment of osteosarcoma.

Vasorelaxant and Antispasmodic Effects of Some Polyphenols and Glycoside in Rat Smooth Muscles

Objective: The present study was undertaken to investigate the effect of Luteolin, chlorogenic acid, amygdalin and tannic acid on vascular smooth muscle contractility. Materials and Methods: The effect of different concentrations of some polyphenols and glycosides on contractile responses of isolated aorta, ileum and trachea to Acetylcholine, KCl and phenylephrine (PE) were evaluated. Results: The results of the current study indicated that luteolin and chlorogenic acid has potent relaxant effects on KCl and PE-induced contractions in rat’s aortic ring. Amygdalin and tannic acid reduced ACh-induced ileum contractions significantly. Conclusions: The inhibitory effect of luteolin and chlorogenic acid on the contraction induced by PE and KCl may be due to their anti-adrenergic and anti-hyperpolarizing effect.

Luteolin inhibits proliferation of human glioblastoma cells via induction of cell cycle arrest and apoptosis

Glioblastoma multiforme (GBM) is a highly malignant brain tumor with limited therapeutic options, and high recurrence and mortality rates. In this study, the anti-tumorigenic properties of luteolin on GBM were examined in vitro. Luteolin was isolated from the whole plant of Glossogyne tenuifolia and the chemical structure was determined by its spectroscopic data. The inhibitory effect of luteolin on the proliferation of GBM 8401 and U87 human glioblastoma cells and the apoptotic effect of this compound on GBM 8401 cells were investigated. Luteolin inhibited the growth of GBM 8401 and U87 cells in a dose- and time-dependent manner. It significantly induced S and G2/M phase cell cycle arrest and apoptotic cell death by decreasing the expression of cyclin-dependent kinase (CDK1), cyclin B1, and anti-apoptotic proteins (Bcl-2, Mcl-1). In addition, luteolin increased the expression of pro-apoptotic proteins (Bid, Bak, Bax, Bad) and activated caspase-3, with a concomitant increased in the levels of cleaved poly-ADP-ribose polymerase (PARP). Moreover, luteolin reduced the cell migration of GBM 8401 cells. Combination treatment of luteolin with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), an anticancer drug used in clinical GBM treatment, enhanced significantly the cytotoxic effect of BCNU in GBM 8401 cells. These results suggest that luteolin may be a potential candidate for GBM adjuvant therapy.

Inhibitory effects of luteolin on human gastric carcinoma xenografts in nude mice and its mechanism

To explore the in vivo anticancer effects of luteolin with BGC-823 gastric carcinoma xenografts in nude mice and elucidate its mechanism. After modeling of gastric carcinoma xenografts in nude mice, 40 BALB/c (nu/nu) nude mice were randomly divided into 5 groups (n = 8 each). And an intraperitoneal injection of luteolin was administered at 10 mg/kg (low-dose), 20 mg/kg (middle-dose) and 40 mg/kg (high-dose) groups. And 5-fluorouracil (30 mg/kg) and control groups were also established. The growth curves of xenografts in nude mice were drawn and weight inhibition rates measured. The morphological features were detected by hematoxylin and eosin staining. And the protein expression levels of vascular endothelial growth factor A (VEGF-A) and matrix metalloproteinase 9 (MMP-9) were measured by immunohistochemistry. In vivo tumor formation test showed that tumor volume in nude mice treated with luteolin was smaller than that of control group. Tumor weights of high-dose luteolin group were lighter than those of the control ((0.29 ± 0.01) vs (0.38 ± 0.03) g). And the difference was statistically significant (P < 0.01). The rate of tumor inhibition in high-dose luteolin group was up to 24.87%. Lymphocytic invasion of tumor tissue was observed under light microscope in the treatment groups. Results of immunohistochemistry showed the positive cell integral of VEGF in middle and high-dose luteolin groups were 1.25 ± 0.17 and 1.00 ± 0.07 respectively. Both were significantly lower than that of control group (1.50 ± 0.15, both P < 0.05). The positive cell integral of MMP-9 in high-dose luteolin group was markedly lower than that of control group (3.75 ± 1.43 vs 9.00 ± 1.08, P < 0.01). Luteolin can effectively inhibit the in vivo growth of gastric tumor. The mechanism may be correlated with the stimulation of immune response and the down-regulated expressions of VEGF-A and MMP-9.

Luteolin Inhibits Angiotensin II-Induced Human Umbilical Vein Endothelial Cell Proliferation and Migration Through Downregulation of Src and Akt Phosphorylation

The proliferation and migration of vascular endothelial cells (VECs) plays a vital role in angiogenesis, a process that influences plaque vulnerability in human atherosclerosis. Luteolin is a type of flavonoid that has shown a positive effect on the morbidity and mortality of cardiovascular diseases. However, it remains unclear whether this compound has a protective effect against the proliferation and migration of human umbilical vein endothelial cells (HUVECs) induced by angiotensin II (AngII). HUVECs were treated with different concentrations of luteolin for varying lengths of time. Analysis using methyl thiazolyl tetrazolium and 5-ethynyl-2'-deoxyuridine revealed that 25 μmol/L luteolin had a particularly inhibitory effect on the AngII-induced proliferation of HUVECs. A Transwell chamber was then used to assay the migration of HUVECs in the presence of 12.5 μmol/L luteolin. The results showed that the migration of AngII-induced HUVECs was also inhibited by luteolin. Further investigations showed that the phosphorylation levels of Src, p-Akt (308), and p-Akt (473) in the group treated with both luteolin and AngII were significantly lower than those of the group treated with only AngII. The inhibitory effects of luteolin on the proliferation and migration of VECs stimulated by AngII are mediated through the downregulation of the PI3K/Akt signaling pathway.