Citrus nobiletin ameliorates experimental colitis by reducing inflammation and restoring impaired intestinal barrier function

Xiong, Yongjian; Chen, Dapeng; Yu, Chunrong; Lv, Bochao; Peng, Jinyong; Wang, Jingyu; Lin, Yuan

doi:10.1002/mnfr.201400614

Cited by 78 publications

(62 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study, we demonstrated that nobiletin prevents the proliferation and migration of glioma cells by inhibiting MAPK and Akt pathways. Recently, nobiletin has attracted a considerable amount of interest because of its multiple biological activities, particularly anti-inflammatory and anticarcinogenic activities (Chien et al, 2015;Guo et al, 2012;Morley et al, 2007;Xiong et al, 2015). Nobiletin has been reported to exhibit an antiproliferative effect and anti-invasive activity against various cancer cells (Chien et al, 2015; Miyamoto et al, 2008;Morley et al, 2007;Shi et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Nobiletin, a Polymethoxylated Flavone, Inhibits Glioma Cell Growth and Migration via Arresting Cell Cycle and Suppressing MAPK and Akt Pathways

et al. 2015

View full text Add to dashboard Cite

Nobiletin, a bioactive polymethoxylated flavone (5,6,7,8,3(') ,4(') -hexamethoxyflavone), is abundant in citrus fruit peel. Although nobiletin exhibits antitumor activity against various cancer cells, the effect of nobiletin on glioma cells remains unclear. The aim of this study was to determine the effects of nobiletin on the human U87 and Hs683 glioma cell lines. Treating glioma cells with nobiletin (20-100 µm) reduced cell viability and arrested the cell cycle in the G0/G1 phase, as detected using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and propidium iodide (PI) staining, respectively; however, nobiletin did not induce cell apoptosis according to PI-annexin V double staining. Data from western blotting showed that nobiletin significantly attenuated the expression of cyclin D1, cyclin-dependent kinase 2, cyclin-dependent kinase 4, and E2 promoter-binding factor 1 (E2F1) and the phosphorylation of Akt/protein kinase B and mitogen-activated protein kinases, including p38, extracellular signal-regulated kinase, and c-Jun N-terminal kinase. Our data also showed that nobiletin inhibited glioma cell migration, as detected by both functional wound healing and transwell migration assays. Altogether, the present results suggest that nobiletin inhibits mitogen-activated protein kinase and Akt/protein kinase B pathways and downregulates positive regulators of the cell cycle, leading to subsequent suppression of glioma cell proliferation and migration. Our findings evidence that nobiletin may have potential for treating glioblastoma multiforme.

show abstract

Section: Discussionmentioning

confidence: 99%

Nobiletin, a Polymethoxylated Flavone, Inhibits Glioma Cell Growth and Migration via Arresting Cell Cycle and Suppressing MAPK and Akt Pathways

et al. 2015

View full text Add to dashboard Cite

show abstract

“…It can been extracted from different citrus species, such as Citrus reticulata Blanco (mandarin orange), Citrus unshiu Markovich, Citrus depressa (shiikuwasa) and Citrus limon (lemon) (2–4). Nobiletin has been reported to be an encouraging antioxidant and anti-inflammatory agent in the treatment of asthma, colitis and Alzheimer's disease (2,5,6). Nobiletin has been reported to protect PC12 cells from hydrogen peroxide (H 2 O 2 )-induced cytotoxicity (7), and to atttenuate ethanol-induced liver injury by augmenting the phosphorylation of AMP-activated protein kinase (AMPK) (8).…”

Section: Introductionmentioning

confidence: 99%

Nobiletin, a citrus flavonoid, activates vasodilator-stimulated phosphoprotein in human platelets through non-cyclic nucleotide-related mechanisms

Jayakumar

Lin

et al. 2016

International Journal of Molecular Medicine

View full text Add to dashboard Cite

Nobiletin, a bioactive polymethoxylated flavone, has been described to possess a diversity of biological effects through its antioxidant and anti-inflammatory properties. Vasodilator-stimulated phosphoprotein (VASP) is a common substrate for cyclic AMP and cyclic GMP-regulated protein kinases [i.e., cyclic AMP-dependent protein kinase (PKA; also known as protein kinase A) and cyclic GMP-dependent protein kinase (PKG; also known as protein kinase G)] and it has been shown to be directly phosphorylated by protein kinase C (PKC). In the present study, we demonstrate that VASP is phosphorylated by nobiletin in human platelets via a non-cyclic nucleotide-related mechanism. This was confirmed by the use of inhibitors of adenylate cyclase (SQ22536) and guanylate cyclase [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)], since they prevented VASP phosphorylation induced by nobiletin. Furthormore, this event was also not affected by specific inhibitors of PKA (H-89), PKG (KT5823) and PKC (Ro318220), representing cyclic nucleotide-dependent pathways upon nobiletin-induced VASP phosphorylation. Similarly, inhibitors of p38 mitogen-activated protein kinase (MAPK; SB203580), extracellular signal-regulated kinase 2 (ERK2; PD98059), c-Jun N-terminal kinase 1 (JNK1; SP600125), Akt (LY294002) and nuclear factor-κB (NF-κB; Bay11-7082) did not affect nobiletin-induced VASP phosphorylation. Moreover, electron spin resonance, dichlorofluorescein fluorescence and western blotting techniques revealed that nobiletin did not affect hydroxyl radicals (OH•), intracellular reactive oxygen species (ROS) and on protein carbonylation, respectively. Furthermore, the nobiletin-induced VASP phosphorylation was surprisingly reversed by the intracellular antioxidant, N-acetylcysteine (NAC), but not by the inhibitor of NADPH oxidase, diphenyleneiodonium chloride (DPI). It was surprising to observe the differential effects of nobiletin and NAC on VASP phosphorylation in human platelets, since they both have been reported to have antioxidant properties. The likely explanation for this discrepancy is that NAC may bind to allosteric sites on the receptor different from those that nobiletin binds to in human platelets. Taken together, our findings suggest that nobiletin induces VASP phosphorylation in human platelets through non-cyclic nucleotide-related mechanisms. Nevertheless, the exact mechanisms responsible for these effects need to be further confirmed in future studies.

show abstract

“…The signalling pathways that nobiletin may interact with were explored in placenta, VAT and skeletal muscle stimulated with TNF ( Figure 4). Nobiletin has been shown to regulate numerous signalling pathways including NF-κB in murine macrophages [42], Akt in intestinal Caco-2 cells [43] and MAPK pathways in human fibroblasts [44]. Therefore, it was of interest to determine if nobiletin also targets these signalling pathways in the present study.…”

Section: Nobiletin Acts Through Nf-κb Akt and Mapk Erk Pathways In Pmentioning

confidence: 97%

Nobiletin exerts anti-diabetic and anti-inflammatory effects in anin vitrohuman model andin vivomurine model of gestational diabetes

et al. 2020

View full text Add to dashboard Cite

Gestational diabetes mellitus (GDM) is a global health issue, whereby pregnant women are afflicted with carbohydrate intolerance with first onset during pregnancy. GDM is characterized by maternal peripheral insulin resistance, thought to be driven by low-grade maternal inflammation. Nobiletin, a polymethoxylated flavonoid, possesses potent glucose-sensitizing and anti-inflammatory properties; however, its effects in GDM have not been assessed. The present study aimed to determine the effects of nobiletin on glucose metabolism and inflammation associated with GDM in both in vitro human tissues and an in vivo animal model of GDM. In vitro, treatment with nobiletin significantly improved TNF-impaired glucose uptake in human skeletal muscle, and suppressed mRNA expression and protein secretion of pro-inflammatory cytokines and chemokines in human placenta and visceral adipose tissue (VAT). Mechanistically, nobiletin significantly inhibited Akt and Erk activation in placenta, and NF-κB activation in VAT. In vivo, GDM mice treated with 50 mg/kg nobiletin daily via oral gavage from gestational day (gd) 1-17 or via i.p. injections from gd 10-17 significantly improved glucose tolerance. Pregnant GDM mice treated with nobiletin from either gd 1-17 or gd 10-17 exhibited significantly suppressed mRNA expression of pro-inflammatory cytokines and chemokines in placenta, VAT and subcutaneous adipose tissue (SAT). Using a quantitative mass spectrometry approach, we identified differentially abundant proteins associated with the effect of nobiletin in vivo. Together, these studies demonstrate that nobiletin improves glucose metabolism and reduces inflammation associated with GDM and may be a novel therapeutic for the prevention of GDM.

show abstract

Citrus nobiletin ameliorates experimental colitis by reducing inflammation and restoring impaired intestinal barrier function

Cited by 78 publications

References 57 publications

Nobiletin, a Polymethoxylated Flavone, Inhibits Glioma Cell Growth and Migration via Arresting Cell Cycle and Suppressing MAPK and Akt Pathways

Nobiletin, a Polymethoxylated Flavone, Inhibits Glioma Cell Growth and Migration via Arresting Cell Cycle and Suppressing MAPK and Akt Pathways

Nobiletin, a citrus flavonoid, activates vasodilator-stimulated phosphoprotein in human platelets through non-cyclic nucleotide-related mechanisms

Nobiletin exerts anti-diabetic and anti-inflammatory effects in anin vitrohuman model andin vivomurine model of gestational diabetes

Contact Info

Product

Resources

About