Umbelliferone prevents isoproterenol-induced myocardial injury by upregulating Nrf2/HO-1 signaling, and attenuating oxidative stress, inflammation, and cell death in rats

The role of oxidative injury and inflammatory response in cardiovascular diseases and heart failure has been well-acknowledged. This study evaluated the protective effect of umbelliferone (UMB), a coumarin with promising radical scavenging and anti-inflammatory activities, on myocardial injury induced by isoproterenol (ISO) in rats. Rats received 50 mg/kg UMB orally for 14 days and 85 mg/kg ISO twice at an interval of 24 h. Administration of ISO elevated serum troponin I, creatine kinase-MB and lactate dehydrogenase, and caused histopathological alterations, including degeneration, fatty vacuolation, myolysis, and atrophy of myocardial fibers. Malondialdehyde (MDA), nitric oxide (NO), nuclear factor-kappaB (NF-κB) p65, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β were increased, whereas reduced glutathione (GSH), superoxide dismutase (SOD), and catalase were decreased in ISO-administered rats. UMB effectively ameliorated myocardial injury, alleviated cardiac function markers, MDA, NO, NF-κB p65, and the inflammatory mediators, and enhanced cellular antioxidants. Bax, caspase-3, and 8-OHdG were decreased, and Bcl-2 was increased in ISO-administered rats treated with UMB. In addition, UMB upregulated nuclear factor-erythroid factor 2-related factor 2 (Nrf2) and heme oxygenase (HO)-1 in the heart of ISO-administered rats. In conclusion, UMB can protect the myocardium from oxidative injury, inflammatory response, and cell death induced by ISO by upregulating Nrf2/HO-1 signaling and antioxidants

Toward understanding the role of aryl hydrocarbon receptor in the immune system: current progress and future trends. Biomed Res Int 2014;2014:520763

The immune system is regulated by distinct signaling pathways that control the development and function of the immune cells. Accumulating evidence suggest that ligation of aryl hydrocarbon receptor (Ahr), an environmentally responsive transcription factor, results in multiple cross talks that are capable of modulating these pathways and their downstream responsive genes. Most of the immune cells respond to such modulation, and many inflammatory response-related genes contain multiple xenobioticresponsive elements (XREs) boxes upstream. Active research efforts have investigated the physiological role of Ahr in inflammation and autoimmunity using different animal models. Recently formed paradigm has shown that activation of Ahr by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 3,3 -diindolylmethane (DIM) prompts the differentiation of CD4 + Foxp3 + regulatory T cells (Tregs) and inhibits T helper (Th)-17 suggesting that Ahr is an innovative therapeutic strategy for autoimmune inflammation. These promising findings generate a basis for future clinical practices in humans. This review addresses the current knowledge on the role of Ahr in different immune cell compartments, with a particular focus on inflammation and autoimmunity

Additional file 1: Figure S1. of Aryl hydrocarbon receptor-microRNA-212/132 axis in human breast cancer suppresses metastasis by targeting SOX4

The role of Ahr in the modulatory effects of TCDD and DIM on migration of MDA-MB-231 and proliferation-based expansion of T47D cells. Figure S2. Effects of DIM on proliferation and adhesion of breast cancer cells. Figure S3. Effects of TCDD and DIM and two additional Ahr agonists on miR-212/132 expression in breast cancer cells. Figure S4. Effects of SOX4 over-expression on the anti-migration, anti-expansion and anti-invasion properties of TCDD and DIM in breast cancer cells. Figure S5. Effects of miR-212/132 mimics on mRNA level of SOX4. Figure S6. Metastasis model efficiency. (PDF 504 kb

Cardiac Protective Effect of Kirenol against Doxorubicin-Induced Cardiac Hypertrophy in H9c2 Cells through Nrf2 Signaling via PI3K/AKT Pathways

Kirenol (KRL) is a biologically active substance extracted from Herba Siegesbeckiae. This natural type of diterpenoid has been widely adopted for its important anti-inflammatory and anti-rheumatic properties. Despite several studies claiming the benefits of KRL, its cardiac effects have not yet been clarified. Cardiotoxicity remains a key concern associated with the long-term administration of doxorubicin (DOX). The generation of reactive oxygen species (ROS) causes oxidative stress, significantly contributing to DOX-induced cardiac damage. The purpose of the current study is to investigate the cardio-protective effects of KRL against apoptosis in H9c2 cells induced by DOX. The analysis of cellular apoptosis was performed using the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining assay and measuring the modulation in the expression levels of proteins involved in apoptosis and Nrf2 signaling, the oxidative stress markers. Furthermore, Western blotting was used to determine cell survival. KRL treatment, with Nrf2 upregulation and activation, accompanied by activation of PI3K/AKT, could prevent the administration of DOX to induce cardiac oxidative stress, remodeling, and other effects. Additionally, the diterpenoid enhanced the activation of Bcl2 and Bcl-xL, while suppressing apoptosis marker proteins. As a result, KRL is considered a potential agent against hypertrophy resulting from cardiac deterioration. The study results show that KRL not only activates the IGF-IR-dependent p-PI3K/p-AKT and Nrf2 signaling pathway, but also suppresses caspase-dependent apoptosis

Genotyping of CYP2C9 and VKORC1 in the Arabic Population of Al-Ahsa, Saudi Arabia

Polymorphisms in the genes encoding CYP2C9 enzyme and VKORC1 reductase significantly influence the dose variability of coumarinic oral anticoagulants (COAs). Substantial inter- and intraethnic variability exists in the frequencies of CYP2C9∗2 and ∗3 and VKORC1 –1639A alleles. However, the prevalence of CYP2C9 and VKORC1 genetic variants is less characterized in Arab populations. A total of 131 healthy adult subjects from the Al-Ahsa region of Saudi Arabia were genotyped for the CYP2C9∗2 and ∗3 and VKORC1 –1639G>A polymorphisms by PCR-RFLP method. The frequencies of the CYP2C9∗2 and ∗3 and VKORC1 –1639A alleles were 13.3%, 2.3%, and 42.4%, respectively, with no subjects carrying 2 defective alleles. The frequencies of the CYP2C9∗3 and VKORC1 –1639A alleles were significantly lower than those reported in different Arabian populations. None of the subjects with the VKORC1 –1639AA genotype were carriers of CYP2C9∗1/∗3 genotypes that lead to sensitivity to COAs therapy. The low frequency of the CYP2C9∗3 allele combined with the absence of subjects carrying 2 defective CYP2C9 alleles suggests that, in this specific population, pharmacogenetic COAs dosing may mostly rely upon VKORC1 genotyping

Activation of aryl hydrocarbon receptor signaling by a novel agonist ameliorates autoimmune encephalomyelitis.

BackgroundMultiple sclerosis (MS) is a widespread neurological autoimmune disease that includes episodes of demyelination in the central nervous system (CNS). The accumulated evidence has suggested that aryl hydrocarbon receptor (Ahr), a ligand-activated transcription factor, is a promising treatment target for MS. Thus, the current study aimed to identify a novel Ahr ligand with anti-inflammatory potential in experimental autoimmune encephalomyelitis (EAE).MethodsAn in silico analysis was carried out to predict interactions between Ahr and potential natural ligands. The effects of a predicted interaction were examined in vitro using CD4+ T cells under T helper17 (Th17) cell-polarizing conditions and lipopolysaccharide (LPS)-stimulated macrophages. Silencing Ahr and microRNA (miR)-132 was achieved by electroporation. Myelin oligodendrocyte glycoprotein (MOG)35-55 and the adoptive transfer of encephalitogenic CD4+ T cells were used to induce EAE.ResultsMolecular docking analysis and in vitro data identified gallic acid (GA) as a novel Ahr ligand with potent activation potential. GA induced the expression of Ahr downstream genes, including cytochrome P450 family 1 subfamily A member 1 (Cyp1a1) and the miR-212/132 cluster, and promoted the formation of the Ahr/Ahr nuclear translocator (Arnt) complex. In vivo, GA-treated mice were resistant to EAE and exhibited reduced levels of proinflammatory cytokines and increased levels of transforming growth factor-β (TGF-β). Furthermore, GA reduced infiltration of CD4+CD45+ T cells and monocytes into the CNS. The anti-inflammatory effects of GA were concomitant with miR-132-potentiated cholinergic anti-inflammation and the regulation of the pathogenic potential of astrocytes and microglia. Inducing EAE by adoptive transfer revealed that CD4+ T cells were not entirely responsible for the ameliorative effects of GA.ConclusionOur findings identify GA as a novel Ahr ligand and provide molecular mechanisms elucidating the ameliorative effects of GA on EAE, suggesting that GA is a potential therapeutic agent to control inflammation in autoimmune diseases such as MS

Novel Aryl Hydrocarbon Receptor Agonist Suppresses Migration and Invasion of Breast Cancer Cells

<div><p>Background</p><p>Despite the remarkable progress to fight against breast cancer, metastasis remains the dominant cause of treatment failure and recurrence. Therefore, control of invasiveness potential of breast cancer cells is crucial. Accumulating evidences suggest Aryl hydrocarbon receptor (Ahr), a helix-loop-helix transcription factor, as a promising target to control migration and invasion in breast cancer cells. Thus, an Ahr-based exploration was performed to identify a new Ahr agonist with inhibitory potentials on cancer cell motility.</p><p>Methods</p><p>For prediction of potential interactions between Ahr and candidate molecules, bioinformatics analysis was carried out. The interaction of the selected ligand with Ahr and its effects on migration and invasion were examined <i>in vitro</i> using the MDA-MB-231 and T47D cell lines. The silencing RNAs were transfected into cells by electroporation. Expressions of microRNAs (miRNAs) and coding genes were quantified by real-time PCR, and the protein levels were detected by western blot.</p><p>Results</p><p>The <i>in silico</i> and <i>in vitro</i> results identified Flavipin as a novel Ahr agonist. It induces formation of Ahr/Ahr nuclear translocator (Arnt) heterodimer to promote the expression of cytochrome P450 family 1 subfamily A member 1 (Cyp1a1). Migration and invasion of MDA-MB-231 and T47D cells were inhibited with Flavipin treatment in an Ahr-dependent fashion. Interestingly, Flavipin suppressed the pro-metastatic factor SRY-related HMG-box4 (Sox4) by inducing miR-212/132 cluster. Moreover, Flavipin inhibited growth and adhesion of both cell lines by suppressing gene expressions of B-cell lymphoma 2 (Bcl2) and integrinα4 (ITGA4).</p><p>Conclusion</p><p>Taken together, the results introduce Flavipin as a novel Ahr agonist, and provide first evidences on its inhibitory effects on cancer cell motility, suggesting Flavipin as a candidate to control cell invasiveness in breast cancer patients.</p></div