Luteolin and luteolin-7-O-glucoside protect against acute liver injury through regulation of inflammatory mediators and antioxidative enzymes in GalN/LPS-induced hepatitic ICR mice

Chung-Mu Park,Young-Sun Song 한국영양학회 2019 Nutrition Research and Practice Vol.13 No.6

BACKGROUND/OBJECTIVES: Anti-inflammatory and antioxidative activities of luteolin and luteolin-7-O-glucoside were compared in galactosamine (GalN)/lipopolysaccharide (LPS)-induced hepatitic ICR mice. MATERIALS/METHODS: Male ICR mice (6 weeks old) were divided into 4 groups: normal control, GalN/LPS, luteolin, and luteolin-7-O-glucoside groups. The latter two groups were administered luteolin or luteolin-7-O-glucoside (50 mg/kg BW) daily by gavage for 3 weeks after which hepatitis was induced by intraperitoneal injection of GalN and LPS (1 g/kg BW and 10 μg/kg BW, respectively). RESULTS: GalN/LPS produced acute hepatic injury by a sharp increase in serum AST, ALT, and TNF-α levels, increases that were ameliorated in the experimental groups. In addition, markedly increased expressions of cyclooxygenase (COX)-2 and its transcription factors, nuclear factor (NF)-κB and activator protein (AP)-1, were also significantly attenuated in the experimental groups. Compared to luteolin-7-O-glucoside, luteolin more potently ameliorated the levels of inflammatory mediators. Phase II enzymes levels and NF-E2 p45-related factor (Nrf)-2 activation that were decreased by GalN/LPS were increased by luteolin and luteolin-7-O-glucoside administration. In addition, compared to luteolin, luteolin-7-O-glucoside acted as a more potent inducer of changes in phase II enzymes. Liver histopathology results were consistent with the mediator and enzyme results. CONCLUSION: Luteolin and luteolin-7-O-glucoside protect against GalN/LPS-induced hepatotoxicity through the regulation of inflammatory mediators and phase II enzymes.

Luteolin and luteolin-7-O-glucoside protect against acute liver injury through regulation of inflammatory mediators and antioxidative enzymes in GalN/LPS-induced hepatitic ICR mice

Park, Chung Mu,Song, Young-Sun The Korean Nutrition Society 2019 Nutrition Research and Practice Vol.13 No.6

BACKGROUND/OBJECTIVES: Anti-inflammatory and antioxidative activities of luteolin and luteolin-7-O-glucoside were compared in galactosamine (GalN)/lipopolysaccharide (LPS)-induced hepatitic ICR mice. MATERIALS/METHODS: Male ICR mice (6 weeks old) were divided into 4 groups: normal control, GalN/LPS, luteolin, and luteolin-7-O-glucoside groups. The latter two groups were administered luteolin or luteolin-7-O-glucoside (50 mg/kg BW) daily by gavage for 3 weeks after which hepatitis was induced by intraperitoneal injection of GalN and LPS (1 g/kg BW and $10{\mu}g/kg\;BW$, respectively). RESULTS: GalN/LPS produced acute hepatic injury by a sharp increase in serum AST, ALT, and $TNF-{\alpha}$ levels, increases that were ameliorated in the experimental groups. In addition, markedly increased expressions of cyclooxygenase (COX)-2 and its transcription factors, nuclear factor $(NF)-{\kappa}B$ and activator protein (AP)-1, were also significantly attenuated in the experimental groups. Compared to luteolin-7-O-glucoside, luteolin more potently ameliorated the levels of inflammatory mediators. Phase II enzymes levels and NF-E2 p45-related factor (Nrf)-2 activation that were decreased by GalN/LPS were increased by luteolin and luteolin-7-O-glucoside administration. In addition, compared to luteolin, luteolin-7-O-glucoside acted as a more potent inducer of changes in phase II enzymes. Liver histopathology results were consistent with the mediator and enzyme results. CONCLUSION: Luteolin and luteolin-7-O-glucoside protect against GalN/LPS-induced hepatotoxicity through the regulation of inflammatory mediators and phase II enzymes.

Luteolin induces apoptosis through endoplasmic reticulum stress and mitochondrial dysfunction in Neuro-2a mouse neuroblastoma cells

Choi, A Young,Choi, Ji Hyun,Yoon, Hana,Hwang, Keun-Young,Noh, Mi Hee,Choe, Wonchae,Yoon, Kyung-Sik,Ha, Joohun,Yeo, Eui-Ju,Kang, Insug Elsevier 2011 european journal of pharmacology Vol.668 No.1

<P><B>Abstract</B></P><P>Luteolin, a dietary flavonoid, induces apoptosis in various types of cancer cells. However, its role in neuroblastoma and the underlying mechanisms remain to be elucidated. In the present study, we investigated the molecular mechanisms of the anti-cancer effect of luteolin in Neuro-2a mouse neuroblastoma cells. Luteolin induced apoptotic cell death and activation of caspase-12, -9, and -3, and knockdown of caspase-12 by siRNA transfection reduced luteolin-induced cell death. Luteolin also induced expression of endoplasmic reticulum (ER) stress-associated proteins, including C/EBP homologous protein (CHOP) and glucose-regulated proteins (GRP) 94 and 78, cleavage of ATF6α, and phosphorylation of eIF2α. CHOP knockdown or ER stress inhibitor, 4-phenylbutyric acid, reduced luteolin-induced cell death. These results suggest involvement of ER stress in luteolin-induced neuroblastoma cell death. We then showed that luteolin induced accumulation of reactive oxygen species and that the anti-oxidant N-acetylcysteine reduced luteolin-induced cell death and expression of CHOP and GRP78. We also demonstrated rapid reduction of mitochondrial membrane potential by luteolin, and N-acetylcysteine, as well as 4-phenylbutyric acid or CHOP siRNA transfection ameliorated luteolin-induced late loss, but not early loss of mitochondrial membrane potential. Finally, we showed that luteolin induced activation of mitogen-activated protein kinases such as JNK, p38, and ERK, and inhibitors of mitogen-activated protein kinases reduced luteolin-induced cell death and CHOP expression, as well as mitochondrial Bax translocation and cytochrome c release. Collectively, our results suggest that luteolin induces apoptosis through ER stress and mitochondrial dysfunction in Neuro-2a mouse neuroblastoma cells.</P>

Anti-inflammatory effects of luteolin: A review of in vitro, in vivo, and in silico studies

Aziz, Nur,Kim, Mi-Yeon,Cho, Jae Youl Elsevier 2018 Journal of Ethnopharmacology Vol.225 No.-

<P><B>Abstract</B></P> <P><B>Ethnopharmacological relevance</B></P> <P>Luteolin (3′, 4′, 5,7-tetrahydroxyflavone) has been identified as commonly present in plants. Plants with a high luteolin content have been used ethnopharmacologically to treat inflammation-related symptoms. Both isolated luteolin and extracts from luteolin-rich plants have been studied using various models and exhibited anti-inflammatory activity.</P> <P><B>Aim of the review</B></P> <P>This paper uses recent research findings with a broad range of study models to describe the anti-inflammatory activity of luteolin, particularly its mechanisms at the molecular level; provide guidance for future research; and evaluate the feasibility of developing luteolin into an anti-inflammatory drug.</P> <P><B>Materials and methods</B></P> <P>We summarize reports about the anti-inflammatory activity of luteolin published since 2009, which we found in MEDLINE/PubMed, Scopus, Web of Knowledge, and Google Scholar. To acquire broad information, we extended our search to online FDA documents.</P> <P><B>Results</B></P> <P>Luteolin is a flavonoid commonly found in medicinal plants and has strong anti-inflammatory activity <I>in vitro</I> and <I>in vivo</I>. Some of its derivatives, such as luteolin-7-O-glucoside, have also shown anti-inflammatory activity. The action mechanism of luteolin varies, but Src in the nuclear factor (NF)-κB pathway, MAPK in the activator protein (AP)− 1 pathway, and SOCS3 in the signal transducer and activator of transcription 3 <B>(</B>STAT3) pathway are its major target transcription factors. A clinical trial with a formulation containing luteolin showed excellent therapeutic effect against inflammation-associated diseases.</P> <P><B>Conclusion</B></P> <P> <I>In silico</I>, <I>in vitro</I>, <I>in vivo</I>, and clinical studies strongly suggest that the major pharmacological mechanism of luteolin is its anti-inflammatory activity, which derives from its regulation of transcription factors such as STAT3, NF-κB, and AP-1. Much work remains to ensure the safety, quality, and efficacy of luteolin before it can be used to treat inflammation-related diseases in humans.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

플라보노이드 luteolin이 세포자멸사 관련 단백질 활성 억제를 통해 6-hydroxydopamine 세포독성에 미치는 억제효과

이선화,강진호,한정호,김두응,이정수 대한신경과학회 2012 대한신경과학회지 Vol.30 No.4

Background: Flavonoid luteolin has been shown to exhibit cell protective effect. However, it is still uncertain whether the effect of luteolin on cellular toxicity of the parkinsonian toxin 6-hydroxydopamine is mediated by apoptosis-related protein activation. Methods: In differentiated PC12 cells exposed to 6-hydroxydopamine in combination with luteolin, we observed the apoptosis-related protein activation, nuclear damage, formation of reactive oxygen species and cell death. Results: 6-Hydroxydopamine caused apoptosis by inducing a decrease in Bid, Bcl-2, Bcl-xL and survivin levels, increase in Bax levels, cytochrome c release and activation of caspases. Treatment with luteolin reduced changes in the apoptosis-related protein levels, formation of reactive oxygen species, nuclear damage and cell death. Conclusions: Luteolin may reduce the 6-hydroxydopamine-induced apoptosis in differentiated PC12 cells by suppressing the activation of the caspase-8- and Bid-dependent pathways and the mitochondria-mediated apoptotic pathway, leading to caspase activation. The preventive effect of luteolin may be associated with its inhibitory effect on the production of reactive oxygen species. Luteolin may attenuate the oxidative stress and mitochondrial dysfunction-induced neuronal cell death take place in Parkinson’s disease. Background: Flavonoid luteolin has been shown to exhibit cell protective effect. However, it is still uncertain whether the effect of luteolin on cellular toxicity of the parkinsonian toxin 6-hydroxydopamine is mediated by apoptosis-related protein activation. Methods: In differentiated PC12 cells exposed to 6-hydroxydopamine in combination with luteolin, we observed the apoptosis-related protein activation, nuclear damage, formation of reactive oxygen species and cell death. Results: 6-Hydroxydopamine caused apoptosis by inducing a decrease in Bid, Bcl-2, Bcl-xL and survivin levels, increase in Bax levels, cytochrome c release and activation of caspases. Treatment with luteolin reduced changes in the apoptosis-related protein levels, formation of reactive oxygen species, nuclear damage and cell death. Conclusions: Luteolin may reduce the 6-hydroxydopamine-induced apoptosis in differentiated PC12 cells by suppressing the activation of the caspase-8- and Bid-dependent pathways and the mitochondria-mediated apoptotic pathway, leading to caspase activation. The preventive effect of luteolin may be associated with its inhibitory effect on the production of reactive oxygen species. Luteolin may attenuate the oxidative stress and mitochondrial dysfunction-induced neuronal cell death take place in Parkinson’s disease.

Rosmarinic acid와 luteolin의 항염증에 대한 상승효과

조병옥(Byoung Ok Cho),윤홍화(Hong Hua Yin),방숭주(Chong Zhou Fang),하혜옥(Hye Ok Ha),김상준(Sang Jun Kim),정승일(Seung Il Jeong),장선일(Seon Il Jang) 한국식품과학회 2015 한국식품과학회지 Vol.47 No.1

본 연구에서는 들깨 유래 기능성 물질인 rosmarinic acid (RA)와 luteolin이 RAW264.7 세포에서 항염증작용에 대한 상승 효과가 있는지 알아보고자 하였다. 그 결과 RAW264.7 세포에 RA (50 μM)와 luteolin (1 μM)을 동시에 처리하였을 경우 염증 매개 인자인 NO, iNOS, PGE2, COX-2의 생성을 RA (100 μM)와 luteolin (2 μM)을 각각 처리하였을 때 보다 더 뛰어나게 억제하였다. 또한 RA (50 μM)와 luteolin (1 μM)을 동시에 처리하였을 경우 TNF-α, IL-6, IL-1β 같은 염증성 사이토카인의 생성량을 RA (100 μM)와 luteolin (2 μM)을 각각 처리하였을 때 보다 더 뛰어나게 억제하는 것을 확인하였다. 그리고 RA (50 μM)와 luteolin (1 μM)을 동시에 처리하였을 경우 RA (100 μM)와 luteolin (2 μM)을 각각 처리하였을 때 보다 NF-κB의 subunit인 p65의 translocation과 IκB-α의 degradation을 더 뛰어나게 억제하는 것을 볼 수 있어 두 화합물 간의 상승작용이 뚜렷함을 확인 할 수 있었고, RA와 luteolin 두 화합물을 동시에 처리할 경우 염증관련 질환 치료에 유용하게 활용될 수 있을 것으로 판단된다. The aim of this study was to investigate the synergistic anti-inflammatory effect of rosmarinic acid (RA) and luteolin from perilla (Perilla frutescens L.) leaves in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. A combination of RA and luteolin more strongly inhibited the production of nitric oxide (NO), inducible NOS (iNOS), prostaglandin E2 (PGE2), and COX-2 than higher concentrations of RA or luteolin alone in LPS-stimulated RAW264.7 macrophages. The combined RA and luteolin synergistically inhibited the production of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), in LPS-stimulated RAW264.7 macrophages. Furthermore, combined RA and luteolin more strongly suppressed NF-κB activation than RA or luteolin alone, by inhibiting the degradation of inhibitor of NF-κB (IκB)-α and nuclear translocation of the p65 subunit of NF-κB in LPS-stimulated RAW264.7 macrophages. Collectively, these results suggest that RA and luteolin in combination exhibit synergistic effects in suppression of LPS-induced inflammation in RAW264.7 macrophages.

RAW264.7 세포에서 새싹보리 및 Luteolin의 히스톤 아세틸기전달효소 활성 억제를 통한 항염증 효능

이재인(Jae-In Lee),정민유(Min-Yu Chung) 한국식품영양과학회 2021 한국식품영양과학회지 Vol.50 No.12

새싹보리의 항염증 효능을 확인하기 위하여 RAW264.7 마우스 대식세포에서 LPS에 의한 NO 생성 억제 정도를 평가하였다. BSP, BSE, BSW 중 BSE와 BSW가 cell viability에 영향을 미치지 않는 농도에서 NO 생성을 억제하였다. 새싹보리 열수 및 에탄올 추출물 모두 항염증 효능이 있음을 확인하였다. 새싹보리의 주요 활성 성분 중 luteolin의 NO 생성 및 in vitro HAT 활성 억제능이 다른 성분들보다 뛰어났다. LPS로 염증반응이 유도된 RAW264.7 세포에서 luteolin은 염증매개인자(IL-6, TNF-α, iNOS, COX-2)의 발현을 감소시켰다. Luteolin의 total 및 specific HAT 활성 조절 정도를 평가하였는데, total HAT 활성에 있어서 luteolin의 IC50은 48.57 μM이었다. Luteolin은 또한 저농도 처리(0.1 μM)에서부터 p300, CBP, PCAF의 활성을 현저하게 감소시켰다. Luteolin의 HAT 활성 억제능은 LPS로 염증반응이 유도된 RAW264.7 세포의 핵 내에서도 동일하게 관찰되었다. Luteolin의 항염증 효능은 HAT 활성 억제와 연관이 있으며, 새싹보리에서 관찰된 항염증 효능은 luteolin의 HAT 억제를 통한 항염증 효능에 기인한다고 할 수 있겠다. This study aimed to assess the anti-inflammatory activity and the mechanism of anti-inflammatory action of barley sprout (Hordeum vulgare L.). Barley sprout powder (BSP), barley sprout ethanol extract (BSE), and barley sprout water extract (BSW) were prepared, and the inhibitory effects of the samples on nitric oxide (NO) production were evaluated. The results showed that the inhibitory activity of BSE and BSW on NO production was greater compared to BSP. Among the active compounds found in barley sprouts, luteolin exhibited greater inhibition of NO production and histone acetyltransferase (HAT) activity compared to the other compounds. Luteolin significantly (P<0.05) attenuated lipopolysaccharide (LPS)-mediated inflammatory mediators, including interleukin-6, tumor necrosis factor-α, inducible nitric oxide synthase, and cyclooxygenase-2 in RAW264.7 cells. Luteolin also significantly inhibited in vitro specific HATs (p300, CBP, PCAF) as well as total HAT, which was also observed in the nuclear fraction of LPS-treated RAW264.7 cells. The anti-inflammatory activity of luteolin was attributed to total and specific HAT inhibition. Collectively, the anti-inflammatory activity of barley sprouts could be attributed to luteolin via HAT inhibition.

Luteolin and luteolin-7-O-glucoside inhibit lipopolysaccharide-induced inflammatory responses through modulation of NF-κB/AP-1/PI3K-Akt signaling cascades in RAW 264.7 cells

Chung Mu Park,Young-Sun Song 한국영양학회 2013 Nutrition Research and Practice Vol.7 No.6

Luteolin is a flavonoid found in abundance in celery, green pepper, and dandelions. Previous studies have shown that luteolin is an anti-inflammatory and anti-oxidative agent. In this study, the anti-inflammatory capacity of luteolin and one of its glycosidic forms, luteolin-7-O-glucoside, were compared and their molecular mechanisms of action were analyzed. In lipopolysaccharide (LPS)-activated RAW 264.7 cells, luteolin more potently inhibited the production of nitric oxide (NO) and prostaglandin E2 as well as the expression of their corresponding enzymes (inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) than luteolin-7-O-glucoside. The molecular mechanisms underlying these effects were investigated to determine whether the inflammatory response was related to the transcription factors, nuclear factor (NF)-κB and activator protein (AP)-1, or their upstream signaling molecules, mitogen-activated protein kinases (MAPKs) and phosphoinositide 3-kinase (PI3K). Luteolin attenuated the activation of both transcription factors, NF-κB and AP-1, while luteolin-7-O-glucoside only impeded NF-κB activation. However, both flavonoids inhibited Akt phosphorylation in a dose-dependent manner. Consequently, luteolin more potently ameliorated LPS-induced inflammation than luteolin-7-O-glucoside, which might be attributed to the differentially activated NF-κB/AP-1/PI3K-Akt pathway in RAW 264.7 cells.

Luteolin의 인간 섬유육종 HT1080 세포에서 ERK 경로를 통한 증식 억제 및 COX-2 발현 유도

권은정,정재창,김송자 대한암예방학회 2012 Journal of cancer prevention Vol.17 No.3

Luteolin is known as the flavone subclass of flavonoids in a variety of plants. Luteolin has been shown a potent anticancer effect in several experiments in vitro. However, the bioavailability of luteolin has not yet been fully tested. Therefore, we investigated the effect of luteolin in human fibrosarcoma HT1080 cells. We found that luteolin inhibited the HT1080 cell viability and proliferation in time-and dose- dependent manner as determined by MTT assay. Also, luteolin dramatically increased the p53 and p21 expression as detected by Western blot analysis. Luteolin induced G2/M phase arrest in HT1080 cells. Moreover, we investigated that luteolin significantly induced COX-2 expression in a time-and dose dependent manner. Phosphorylation of ERK was considerably increased by luteolin in HT1080 cells. Inhibition of ERK with PD98059 suppressed luteolin induced p53, p21 and COX-2 expression. Our results suggest that luteolin regulates p53/p21 dependent cell proliferation and COX-2 expression through ERK pathway in HT1080 human fibrosarcoma cells.

Sleep Promoting Effect of Luteolin in Mice via Adenosine A1 and A2A Receptors

( Tae-ho Kim ),( Raly James Custodio ),( Jae Hoon Cheong ),( Hee Jin Kim ),( Yi-sook Jung ) 한국응용약물학회 2019 Biomolecules & Therapeutics(구 응용약물학회지) Vol.27 No.6

Luteolin, a widespread flavonoid, has been known to have neuroprotective activity against various neurologic diseases such as epilepsy, and Alzheimer’s disease. However, little information is available regarding the hypnotic effect of luteolin. In this study, we evaluated the hypnotic effect of luteolin and its underlying mechanism. In pentobarbital-induced sleeping mice model, luteolin (1, and 3 mg/kg, p.o.) decreased sleep latency and increased the total sleep time. Through electroencephalogram (EEG) and electromyogram (EMG) recording, we demonstrated that luteolin increased non-rapid eye movement (NREM) sleep time and decreased wake time. To evaluate the underlying mechanism, we examined the effects of various pharmacological antagonists on the hypnotic effect of luteolin. The hypnotic effect of 3 mg/kg of luteolin was not affected by flumazenil, a GABAA receptorbenzodiazepine (GABAAR-BDZ) binding site antagonist, and bicuculine, a GABAAR-GABA binding site antagonist. On the other hand, the hypnotic effect of 3 mg/kg of luteolin was almost completely blocked by caffeine, an antagonist for both adenosine A1 and A2A receptor (A1R and A2AR), 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), an A1R antagonist, and SCH-58261, an A2AR antagonist. From the binding affinity assay, we have found that luteolin significantly binds to not only A1R but also A2AR with IC₅₀ of 1.19, 0.84 µg/kg, respectively. However, luteolin did not bind to either BDZ-receptor or GABAAR. From these results, it has been suggested that luteolin has hypnotic efficacy through A1R and A2AR binding.