Flavonoid Fraction of Bergamot Juice Reduces LPS-Induced Inflammatory Response through SIRT1-Mediated NF-κB Inhibition in THP-1 Monocytes

Risitano, Roberto; Currò, Monica; Cirmi, Santa; Ferlazzo, Nadia; Campiglia, Pietro; Caccamo, Daniela; Ientile, Riccardo; Navarra, Michele

doi:10.1371/journal.pone.0107431

Cited by 109 publications

(99 citation statements)

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“…Additionally, S100A4 induced an inflammatory response partially mediated by activation of NF-κB in mononuclear cells from patients with RA (43). on the contrary, bergamot juice can inhibit LPS-induced proinflammatory cytokines involved in the inhibition of NF-κB activation (40). In accordance with these studies, our data showed that S100A8 significantly activated the nF-κB pathway in macrophages in the inflammatory microenvironment and promoted both gene expression and secretion of inflammatory cytokines (IL-1β and TNF-α).…”

Section: Discussionmentioning

confidence: 97%

“…It is well known that the nF-κB signaling pathway plays a crucial role in immune-regulation and inflammatory response via the induction of inflammatory cytokines (such as IL-6, IL-1β and TNF-α), cyclooxygenase-2 (CoX-2) and inducible nitric oxide synthase (inoS) (40). For instance, transcriptional activity of nF-κB may be most critical in S100A8/A9-induced expression of proinflammatory cytokines in monocytes/macrophages (41).…”

Section: Discussionmentioning

confidence: 99%

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S100A8 facilitates the migration of colorectal cancer cells through regulating macrophages in the inflammatory microenvironment

Zha

Sun

et al. 2016

Oncology Reports

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Abstract.Previous studies have shown that S100 calcium-binding protein A8 (S100A8) contributes to the survival and migration of colorectal cancer (CRC) cells. However, whether S100A8 participates in the progression and metastasis of CRC via the regulation of macrophages in the tumor inflammatory microenvironment remains unknown. In this study, phorbol myristate acetate (PMA) was used to induce the differentiation of THP-1 monocytes to macrophages. MTT assay, western blot analysis, immunofluorescence staining, semi-quantitative RT-PCR (semi-PCR), quantitative real-time PCR (qPCR), Gaussia luciferase activity assay and ELISA were performed to analyze the roles and molecular mechanisms of S100A8 in the modulation of macrophages. MTT assay, flow cytometric analysis, Hoechst staining, wound healing and Transwell migration assay were used to test the effect of S100A8 on the viability and migration of CRC cells co-cultured with macrophages in the inflammatory microenvironment. We found that THP-1 monocytes were induced by PMA and differentiated to macrophages. S100A8 activated the NF-κB pathway in the macrophages and promoted the expression of miR-155 and inflammatory cytokines IL-1β and TNF-α in the inflammatory microenvironment mimicked by lipopolysaccharides (LPS). Furthermore, S100A8 contributed to augment the migration but not the viability of the CRC cells co-cultured with the macrophages in the inflammatory microenvironment. Altogether, our study demonstrated that S100A8 facilitated the migration of CRC cells in the inflammatory microenvironment, and the underlying molecular mechanisms may be partially attributed to the overexpression of miR-155, IL-1β and TNF-α through activation of the NF-κB pathway in macrophages. IntroductionColorectal cancer (CRC), for which distant metastasis accounts for the leading cause of cancer mortality, is one of the most malignant gastrointestinal carcinomas worldwide (1). The pathogenesis of CRC is a complex process and involves environmental influences, genetic alterations, and the host immune system and their interactions. The formation of an inflammatory microenvironment also plays a pivotal role in the development of CRC (2). The host microenvironment is comprised of numerous infiltrating immune cell types and resident tumor cells. Among the immune cells, macrophages play an indispensable role. For instance, macrophage infiltration in colon tissue has been observed in both inflammatory bowel disease (IBD) and CRC (4), and the cytokines secreted by macrophages under certain conditions have directly or indirectly stimulated inflammation and tumor progression (5,6). Although great progress has been made, the interactions and the molecular mechanisms between CRC and the inflammatory microenvironment remain unknown. S100A8 (calgranulin A or S100 calcium-binding protein A8) is a member of the low-molecular calcium binding S100 protein family. It also belongs to the family of damage-associated molecular patterns (DAMPs). Studies have shown that S100A8 plays an important role in regul...

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

S100A8 facilitates the migration of colorectal cancer cells through regulating macrophages in the inflammatory microenvironment

Zha

Sun

et al. 2016

Oncology Reports

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“…While this fruit is primarily used in the fragrance industry for its essential oil extracted from its peel, recent studies on the juice from the endocarp of bergamot have shown that it has several bioactivities such as antioxidant, antiinflammatory, cytotoxic, neuroprotective, as well as hypolipidemic and hypoglycemic properties (Currò et al 2016;Impellizzeri et al 2015;Miceli et al 2007;Mollace et al 2008;Risitano et al 2014;Sicari et al 2016;Trovato et al 2010;Tundis et al 2012). From clinical and mechanistic studies, it has been proposed (Mollace et al 2011) that melitidine and brutieridine in concert with naringin and other flavonone glycosides might be responsible for the hypolipidemic effects of BFE and function as do the statin drugs through the direct action on 3-hydroxy-3-methyl-glutaryl -coenzyme A (HMG-CoA) reductase activity.…”

Section: Introductionmentioning

confidence: 99%

Synergistic in vitro antioxidant activity and observational clinical trial of F105, a phytochemical formulation includingCitrus bergamia, in subjects with moderate cardiometabolic risk factors

Babish¹,

Dahlberg

et al. 2016

Can. J. Physiol. Pharmacol.

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Abstract:We examined the clinical safety and efficacy of F105 in 11 subjects with moderate dyslipidemia. F105 is a combination of bergamot fruit extract (Citrus bergamia, BFE) and 9 phytoextracts selected for their ability to improve the antioxidant and anti-inflammatory activity of BFE. In vitro F105 exhibited a synergistic inhibition of oxygen radical absorbing capacity, peroxynitrite formation, and myeloperoxidase activity. Following 12 weeks of F105 daily, no treatment-related adverse events or changes in body mass were seen. Statistically significant changes were noted in total cholesterol (−7.3%), LDL-cholesterol (−10%), non-HDL cholesterol (−7.1%), cholesterol/HDL (−26%), and apolipoprotein B (−2.8%). A post hoc analysis of 8 subjects with HbA1c > 5.4 and HOMA-IR score > 2 or elevated triglycerides revealed additional statistically significant changes in addition to those previously observed in all subjects including triglycerides (−27%), oxLDL (−19%), LDL/HDL (−25%), triglycerides/HDL (−27%), oxLDL/HDL (−25%), and PAI-1 (−37%). A follow-up case report of a 70-year-old female patient, nonresponsive to statin therapy and placed on F105 daily, demonstrated improved cardiometabolic variables over 12 weeks similar to the subgroup. In summary, F105 was clinically well-tolerated and effective for ameliorating dyslipidemia in subjects with moderate cardiometabolic risk factors, particularly in the individuals with HbA1c > 5.4%.Key words: cardiometabolic disease, bergamot, antioxidant, myeloperoxidase, oxidized LDL, dyslipidemia, HbA1c. Résumé :Les auteurs ont examiné la sécurité et l'efficacité cliniques du F105 chez 11 sujets présentant une dyslipidémie modérée. Le F105 est une combinaison d'extrait de bergamote (Citrus bergamia, EB) et 9 extraits végétaux sélectionnés pour leur capacité à améliorer l'activité antioxydante et anti-inflammatoire de l'EB. In vitro, le F105 montrait une inhibition synergique de la capacité d'absorption des radicaux d'oxygène, de formation de peroxynitrite et de l'activité myéloperoxydase. Après 12 semaines d'administration quotidienne de F105, aucun effet secondaire indésirable relié au traitement ou changements de poids corporels n'étaient observés. Des changements statistiquement significatifs ont été notés quant au cholestérol total (−7,3 %), LDL-cholestérol (−10 %), non-HDL-cholestérol (−7,1 %), cholestérol/HDL (−26 %) et apolipoprotéine B (−2,8 %). Une analyse post hoc de 8 sujets présentant une HbA1c > 5.4 et un indice HOMA-IR >2 ou des triglycérides élevés a révélé des changements additionnels statistiquement significatifs en plus de ceux précédemment observés chez tous les sujets incluant les triglycérides (−27 %), oxLDL (−19 %), LDL/HDL (−25 %) triglycérides/HDL (−27 %), oxLDL/HDL (−25 %), et PAI-1 (−37 %). Une étude de cas de suivi d'une patiente de 70 ans, ne répondant pas à la thérapie par les statines et traitée au F105 quotidiennement, a démontré amélioration des variables cardiométaboliques pendant les 12 semaines similaire au sous-groupe. En résumé, le F105 est bie...

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“…LPS is a well-characterized inducer of inflammatory response and the pro-inflammatory activity of LPS-induced TLR4 expression plays an important role in pathological responses in autoimmune disorders and chronic inflammatory conditions, with the development of atherosclerosis, neurodegenerative diseases, and other chronic diseases [4]. Once activated, TLR4 initiates downstream signaling pathways [mitogen-activated protein kinases (MAPKs) and nuclear factor κB (NF-κB)], resulting in the release of cytokines such as interleukin (IL)-6, IL-1β, IL-8, IL-12p40, tumor necrosis factor (TNF)-α, IL-18, and NO, which then mediate the innate immune response and inflammatory response [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…Monocytes are key cells of the innate immune system and are responsible for the initiation, progression and resolution of inflammation, pathogen clearance, wound healing, and tissue homeostasis [6,15]. THP-1 is widely used as a model to study inflammatory response.…”

Section: Introductionmentioning

confidence: 99%

Parthenolide inhibits LPS-induced inflammatory cytokines through the toll-like receptor 4 signal pathway in THP-1 cells

Li¹,

Gao²,

Wu³

et al. 2015

ABBS

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Parthenolide (PTL) shows potent anti-inflammatory and anti-cancer activities. In the present study, the molecular mechanisms of PTL's activities were explored in lipopolysaccharide (LPS)-induced human leukemia monocytic THP-1 cells and human primary monocytes. The 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt (MTS) assay was used to analyze the effect of PTL on THP-1 cell viability. Enzyme-linked immunosorbent assay was used to determine the effect of PTL on LPS-induced inflammatory cytokine secretion. Flow cytometry and quantitative real-time polymerase chain reaction were used to assess the effect of PTL on LPSinduced toll-like receptor 4 (TLR4) expression. Phosphorylation levels of signaling molecules were determined by western blot analysis. Results showed that PTL <12.5 μM did not significantly affect THP-1 cells viability. LPS treatment led to a marked up-regulation of interleukin (IL)-6, IL-1β, IL-8, IL-12p40, tumor necrosis factor-α, IL-18, and NO in THP-1 cells. However, PTL inhibited the expression of these cytokines in a dose-dependent manner, with IC 50 values of 1.091-2.620 μM. PTL blocked TLR4 expression with an IC 50 value of 1.373 μM as determined by the flow cytometry analysis, and this blocking effect was verified at both protein and mRNA levels. Up-regulation of phosphorylation levels of extracellular signal-regulated kinase 1/2, Jun N-terminal kinase, p38, nuclear factor κB (NF-κB) p65, and IκBα and up-regulation of expressions of other molecules (inducible nitric oxide synthase, TLR4, and TNF receptor-associated factor 6) induced by LPS were abolished by PTL in a dose-dependent manner. The anti-inflammatory mechanisms of PTL operate partly through the TLR4-mediated mitogen-activated protein kinase and NF-κB signaling pathways. Therefore, TLR4 may be a new target for anti-inflammation therapies.

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Flavonoid Fraction of Bergamot Juice Reduces LPS-Induced Inflammatory Response through SIRT1-Mediated NF-κB Inhibition in THP-1 Monocytes

Cited by 109 publications

References 41 publications

S100A8 facilitates the migration of colorectal cancer cells through regulating macrophages in the inflammatory microenvironment

S100A8 facilitates the migration of colorectal cancer cells through regulating macrophages in the inflammatory microenvironment

Synergistic in vitro antioxidant activity and observational clinical trial of F105, a phytochemical formulation includingCitrus bergamia, in subjects with moderate cardiometabolic risk factors

Parthenolide inhibits LPS-induced inflammatory cytokines through the toll-like receptor 4 signal pathway in THP-1 cells

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