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

Aging is a major risk factor in the development of chronic diseases affecting various tissues including the cardiovascular system, muscle and bones. Age-related diseases are a consequence of the accumulation of cellular damage and reduced activity of protective stress response pathways leading to low-grade systemic inflammation and oxidative stress. Both inflammation and oxidative stress are major contributors to cellular senescence, a process in which cells stop proliferating and become dysfunctional by secreting inflammatory molecules, reactive oxygen species (ROS) and extracellular matrix components that cause inflammation and senescence in the surrounding tissue. This process is known as the senescence associated secretory phenotype (SASP). Thus, accumulation of senescent cells over time promotes the development of age-related diseases, in part through the SASP. Polyphenols, rich in fruits and vegetables, possess antioxidant and anti-inflammatory activities associated with protective effects against major chronic diseases, such as cardiovascular disease (CVD). In this review, we discuss molecular mechanisms by which polyphenols improve anti-oxidant capacity, mitochondrial function and autophagy, while reducing oxidative stress, inflammation and cellular senescence in vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). We also discuss the therapeutic potential of polyphenols in reducing the effects of the SASP and the incidence of CVD.

Protective Role of Polyphenols against Vascular Inflammation, Aging and Cardiovascular Disease.

Diet-induced obesity is associated with low-grade inflammation, which, in most cases, leads to the development of metabolic disorders, primarily insulin resistance and type 2 diabetes. Although prior studies have implicated the adipose tissue as being primarily responsible for obesity-associated inflammation, the latest discoveries have correlated impairments in intestinal immune homeostasis and the mucosal barrier with increased activation of the inflammatory pathways and the development of insulin resistance. Therefore, it is essential to define the mechanisms underlying the obesity-associated gut alterations to develop therapies to prevent and treat obesity and its associated diseases. Flavonoids appear to be promising candidates among the natural preventive treatments that have been identified to date. They have been shown to protect against several diseases, including CVD and various cancers. Furthermore, they have clear anti-inflammatory properties, which have primarily been evaluated in non-intestinal models. At present, a growing body of evidence suggests that flavonoids could exert a protective role against obesity-associated pathologies by modulating inflammatory-related cellular events in the intestine and/or the composition of the microbiota populations. The present paper will review the literature to date that has described the protective effects of flavonoids on intestinal inflammation, barrier integrity and gut microbiota in studies conducted using in vivo and in vitro models.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/C32467493BB55E5C3C2A119641F6FB84/S0954422416000159a.pdf/div-class-title-effects-of-flavonoids-on-intestinal-inflammation-barrier-integrity-and-changes-in-gut-microbiota-during-diet-induced-obesity-div.pdf

Effects of flavonoids on intestinal inflammation, barrier integrity and changes in gut microbiota during diet-induced obesity.

Antiviral activity of luteolin against Japanese encephalitis virus

It is currently believed that inflammation plays a central role in the pathophysiology of atherosclerosis (AS). Oxidative stress and redox-sensitive transcription factors are implicated in the process. Ginsenoside Rb1, a major active ingredient in processed Radix notoginseng, has attracted widespread attention because of its potential to improve cardiovascular function. However, the effects of ginsenoside Rb1 on tumor necrosis factor α (TNF-α)-induced vascular endothelial cell injury and the underlying molecular mechanisms have never been studied. This study showed that TNF-α-induced oxidative stress, inflammation and apoptosis in human umbilical vein endothelial cells (HUVECs) could be attenuated by ginsenoside Rb1 pretreatment. Using JC-1, Annexin V/PI and TUNEL staining, and a caspase-3 activity assay, we found that Rb1 provided significant protection against TNF-α-induced cell death. Furthermore, Rb1 pretreatment could inhibit TNF-α-induced ROS and MDA production; increase the activities of SOD, CAT and GSH-Px; and decrease the levels of IL-1β, IL-6, VCAM-1, ICAM-1, VEGF, MMP-2 and MMP-9. Importantly, the cytoprotective effects of Rb1 were correlated with NF-κB signaling pathway inhibition. Additionally, we found that Rb1 may suppress the NF-κB pathway through p-38 and JNK pathway activation, findings supported by the results of our experiments involving anisomycin (AM), a JNK and p38 activator. In conclusion, this study showed that ginsenoside Rb1 protects HUVECs from TNF-α-induced oxidative stress and inflammation by inhibiting JNK and p38. This inhibition suppressed NF-κB signaling and down-regulated the expression of inflammatory factors and apoptosis-related proteins.

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Attenuation of TNF-α-Induced Inflammatory Injury in Endothelial Cells by Ginsenoside Rb1 via Inhibiting NF-κB, JNK and p38 Signaling Pathways.

Vascular inflammation plays a significant role in the pathogenesis of atherosclerosis. Luteolin, a naturally occurring flavonoid present in many medicinal plants and some commonly consumed fruits and vegetables, has received wide attention for its potential to improve vascular function in vitro. However, its effect in vivo and the molecular mechanism of luteolin at physiological concentrations remain unclear. Here, we report that luteolin as low as 0.5 μM significantly inhibited tumor necrosis factor (TNF)-α-induced adhesion of monocytes to human EA.hy 926 endothelial cells, a key event in triggering vascular inflammation. Luteolin potently suppressed TNF-α-induced expression of the chemokine monocyte chemotactic protein-1 (MCP-1) and adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), key mediators involved in enhancing endothelial cell-monocyte interaction. Furthermore, luteolin inhibited TNF-α-induced nuclear factor (NF)-κB transcriptional activity, IκBα degradation, expression of IκB kinase β and subsequent NF-κB p65 nuclear translocation in endothelial cells, suggesting that luteolin can inhibit inflammation by suppressing NF-κB signaling. In an animal study, C57BL/6 mice were fed a diet containing 0% or 0.6% luteolin for 3 weeks, and luteolin supplementation greatly suppressed TNF-α-induced increase in circulating levels of MCP-1/JE, CXCL1/KC and sICAM-1 in C57BL/6 mice. Consistently, dietary intake of luteolin significantly reduced TNF-α-stimulated adhesion of monocytes to aortic endothelial cells ex vivo. Histology shows that luteolin treatment prevented the eruption of endothelial lining in the intima layer of the aorta and preserved elastin fibers' delicate organization as shown by Verhoeff-Van Gieson staining. Immunohistochemistry studies further show that luteolin treatment also reduced VCAM-1 and monocyte-derived F4/80-positive macrophages in the aorta of TNF-α-treated mice. In conclusion, luteolin protects against TNF-α-induced vascular inflammation in both in vitro and in vivo models. This anti-inflammatory effect of luteolin may be mediated via inhibition of the NF-κB-mediated pathway.

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Luteolin protects against vascular inflammation in mice and TNF-alpha-induced monocyte adhesion to endothelial cells via suppressing IΚBα/NF-κB signaling pathway

OBJECTIVE Osteosarcoma is one of the most common primary bone malignancies. Long non-coding RNAs (lncRNAs) have recently emerged as key regulators of osteosarcoma. The aim of present study was to explore the prognostic value of long non-coding RNA XIST (XIST) in osteosarcoma and XIST's relation to the cell proliferation in osteosarcoma in vitro. PATIENTS AND METHODS The XIST expressions were detected in osteosarcoma tissues and their paired adjacent normal tissues from 145 osteosarcoma patients by using qRT-PCR. The association between XIST expression and clinicopathological factors, as well as survival rates, was analyzed. The possibility of XIST as a prognostic biomarker for osteosarcoma was examined by Cox proportional hazard regression model. MTT assays were conducted to explore the impact of XIST overexpression on the proliferation of osteosarcoma cells. RESULTS The results showed that XIST was significantly up-regulated in osteosarcoma tissues and cell lines, and high XIST expression was significantly associated with advanced tumor size (p=0.009), advanced clinical stage (p=0.001) and present distant metastasis (p=0.009). Kaplan-Meier analysis showed that increased XIST expression was associated with poor overall survival of patients. Univariate and multivariate analysis suggested that XIST expression was an independent prognostic factor for the survival of patients with osteosarcoma. Furthermore, we found that knockdown of XIST significantly suppressed the proliferation of osteosarcoma cells in vitro. CONCLUSIONS XIST was suggested to have a tumor promoter effect, and thus, to be a predictor of outcome in patients with osteosarcoma.

High expression of long non-coding RNA XIST in osteosarcoma is associated with cell proliferation and poor prognosis.

Highly flexible proteins present a special challenge for structure determination because they are multi-structured yet not disordered, so their conformational ensembles are essential for understanding function. Because spectroscopic measurements of multiple conformational populations often provide sparse data, experiment selection is a limiting factor in conformational refinement. A molecular simulations- and information-theory based approach to select which experiments best refine conformational ensembles has been developed. This approach was tested on three flexible proteins. For proteins where a clear mechanistic hypothesis exists, experiments that test this hypothesis were systematically identified. When available data did not yield such mechanistic hypotheses, experiments that significantly outperform structure-guided approaches in conformational refinement were identified. This approach offers a particular advantage when refining challenging, underdetermined protein conformational ensembles.

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Refinement of Highly Flexible Protein Structures using Simulation‐Guided Spectroscopy

Objective To investigate the effects of telmisartan on matrix metalloproteinase-9 (MMP-9) expression in macrophages induced by angiotensin II (Ang II) and its mechanism. Materials and methods THP-1 cells were adopted for research, and phorbol-12-myristate-13-acetate (PMA) was utilized to induce THP-1 cells to be transformed into macrophages, with Ang II as a stimulating factor and telmisartan as a therapeutic drug. Cell counting kit-8 (CCK8) and lactate dehydrogenase (LDH) were applied to detect cell viability and toxicity. Enzyme-linked immunosorbent assay (ELISA) was performed to measure the MMP-9 release level. Polymerase Chain Reaction (PCR) and Western blotting were conducted to detect the expressions of MMP-9 messenger ribonucleic acid (mRNA) and protein, respectively. The mechanism of action was further studied, and the activity of cyclooxygenase-2 (COX2)/macrophage-expressed gene 1 (mPEG1) pathway was determined via PCR and Western blotting. Results The 1 mM Ang II could remarkably activate the synthesis and release of MMP-9 as well as the COX2/mPEG1 pathway in macrophages. However, telmisartan could effectively repress the Ang II-induced MMP-9 synthesis and release in the macrophages, and suppress the COX2/mPEG1 pathway in the macrophages activated by Ang II. Conclusions Telmisartan can inhibit the activation of MMP-9 in the macrophages by suppressing the COX2/mPEG1 pathway.

Telmisartan inhibits Ang II-induced MMP-9 expression in macrophages in stabilizing atheromatous plaque.

BACKGROUND: Traumatic brain injury (TBI) is a serious neurodisorder commonly caused by sports related events or violence. It is the leading cause of disability in people under 40 . AIM: In order to elucidate the molecular mechanism of the secondary injury afterTBI. MATERIALS AND METHODS: In this study, we downloaded gene expression profile on TBI model with sham controls for gene set enrich - ment analysis and pathway analysis. RESULTS: At a q-value of 5%, 361 genes were up-regulated and 373 were down-regulated in samples obtained at 48 hours after TBI. Func - tional analyses revealed that steroid biosynthe - sis, cell cycle, metal ion transport, inflammation and apoptosis were significantly dysregulated during the late period after trauma. In addition, MAPK3 (mitogen-activated protein kinase 3), was identified as the hub node in the protein- protein interaction (PPI) network constructed by the differentially expressed genes (DEGs). CONCLUSIONS: Further elucidation of genes and proteins in our study may reveal their poten - tial as novel therapeutic targets.

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Jason Z. Li

Papers

Luteolin protects against vascular inflammation in mice and TNF-alpha-induced monocyte adhesion to endothelial cells via suppressing IΚBα/NF-κB signaling pathway

High expression of long non-coding RNA XIST in osteosarcoma is associated with cell proliferation and poor prognosis.

Refinement of Highly Flexible Protein Structures using Simulation‐Guided Spectroscopy

Telmisartan inhibits Ang II-induced MMP-9 expression in macrophages in stabilizing atheromatous plaque.

Bioinformatics analysis of gene expression profiles in the rat cerebral cortex following traumatic brain injury.