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In this study, it was aimed to elucidate the interaction between aryl hydrocarbon receptor (AHR), nuclear factor-kappa B (NF-kB), and cytochrome P4501A1 (CYP1A1) with hepatitis B virus X protein (HBX) in a human liver cancer cell line (HepG2) transfected with HBX. First, AHR, NF-kB, and CYP1A1 genes were cloned into the appropriate region of the CheckMate mammalian two-hybrid recipient plasmids using a flexi vector system. Renilla and firefly luciferases were quantified using the dual-luciferase reporter assay system to measure the interactions. Secondly, transient transfections of CYP1A1 and NF-kB (RelA) were performed into HBX–positive and HBX–negative HepG2 cells. The mRNA expression of CYP1A1 and NF-kB genes were confirmed with RT-PCR, and cell viability was measured by WST-1. Further verification was assessed by measuring the activity and protein level of CYP1A1. Additionally, CYP1A1/HBX protein–protein interactions were performed with co-immunoprecipitation, which demonstrated no interaction. These results have clearly shown that the NF-kB and AHR genes interact with HBX without involving CYP1A1 and HBX protein–protein interactions. The present study confirms that AHR and NF-kB interaction plays a role in the HBV mechanism mediated via HBX and coordinating the carcinogenic or inflammatory responses; still, the CYP1A1 gene has no effect on this interaction. © 2022 Elsevier B.V.

In this study, cerium oxide nanoparticles (CONPs) were synthesized using fresh green walnut shell extract in microwave environment. The morphology and structure of the CONPs were determined using ultraviolet-visible (UV/VIS), attenuated total reflection-Fourier transform infrared (ATR-FT-IR), X-ray diffraction (XRD), energy-dispersive X-ray (EDX) spectroscopy, and scanning electron microscopy (SEM). Crystal purple staining, Annexin V-FITC detection, RT-PCR, P53, and NF-?B luciferase reporter assays were performed to evaluate the mechanism of action of CONPs in breast cancer cell lines (MCF7). The biosynthesized CONPs showed cytotoxic effects and induced apoptosis in MCF7 cells. Furthermore, CONPs induced P53 expression and suppressed NF-?B gene expression, both of which were confirmed using reporter assays. Based on the present results, it was concluded that CONPs can induce apoptosis by acting on P53 at the transcriptional level and may cause cell death by suppressing NF-?B-mediated transcription. © 2022 Wiley-VHCA AG, Zurich, Switzerland.

WOS: 000530769000001, PubMed: 32378168, The importance of microbial natural compounds in drug research is increasing every year and they are used to prevent or treat a variety of diseases. Hypomyces chrysospermus is a cosmopolitan parasite of many Boletaceae members. Since not much work has been conducted to date, this study is undertaken to explore the anticancer effect, including the antiproliferative and antimetastatic activity of Hypomyces chrysospermus. the aim of this study is to determine the antiproliferative and antimetastatic activity of Hypomyces chrysospermus ethyl acetate extract, having antioxidant activity, against A549, Caco2, MCF-7 human cancer and CCD-19 Lu and CCD 841 CoN healthy human cell lines. Firstly, cytotoxic activity was determined by the WST-1 assay. After cell proliferations and anti-metastatic effects were investigated by a real-time cell analysis system (RTCA-DP) and IC50 concentrations were calculated for each cell line. in addition, the expression levels of Apaf-1, TNF and NF-kB mRNA in cancer cells were investigated with RealTime-PCR. the ethyl acetate extract of Hypomyces chrysospermus presented anticancer activities including antiproliferative and antimetastatic effects. Hypomyces chrysospermus as a source of biologically active metabolites can be used as an important resource in the development of new anticancer effective agents., Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [113Z746], This work was supported by the Scientific and Technological Research Council of Turkey (TUBITAK) under Grant No. 113Z746. the authors extend their thanks to Dr. Bukay Yenice Gursu for technical contribution of the dendrogram.

We read with great interest the article “Obesity as a risk factor for unfavorable outcomes in critically ill patients affected by COVID-19”, and we believe this is an important contribution toward understanding the relationship between the severity of the disease COVID-19 and obesity. Although we agree on the apparent role of adipokines, we believe that there is evidence suggesting that leptin may have a significant role in the underlying mechanisms of severe COVID-19 in obese patients due to its important immunological function...

Asbestos is one of the most important occupational carcinogens. Currently, about 125 million people worldwide are exposed to asbestos in the workplace. According to global estimates, at least 107,000 people die each year from lung cancer, mesothelioma, and asbestosis as a result of occupational exposure to asbestos. The high pathogenicity of this material is currently known, being associated with the development of pulmonary diseases, of which lung cancer is the main cause of death due to exposure to this mineral. Pulmonary diseases related to asbestos are a common clinical problem and a major health concern worldwide. Extensive research has identified many important pathogenic mechanisms; however, the precise molecular mechanisms involved, and the generated genomic damage that lead to the development of these diseases, are not completely understood. The modes of action that underlie this type of disease seem to differ depending on the type of fiber, lung clearance, and genetics. This evidences the need to increase our knowledge about these effects on human health. This review focuses on the characteristics of asbestos and the cellular and genomic damage generated in humans via exposure. © 2019 Zhang et al.

Vogt, Bruno/0000-0002-1548-6387; Dufek, Stephanie/0000-0002-6323-6673; Liu, Lili/0000-0002-2622-9669; Paczek, Leszek/0000-0003-0160-3009; Cui, Zhao/0000-0002-5837-1926; amoroso, antonio/0000-0002-9437-9407; Rosen, Raphael/0000-0003-1025-1965; Loos, Ruth/0000-0002-8532-5087; coenen, marieke/0000-0001-8796-2031; zanoni, francesca/0000-0001-9567-6713; CUCCA, Francesco/0000-0002-7414-1995; Ars, Elisabet/0000-0002-4118-4358; Hamilton, Patrick/0000-0001-6703-3745 WOS:000563559600001 PubMed ID: 32231244 Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 x 10(-12)) and IRF4 (rs9405192, OR = 1.29, P = 1.4 x 10(-14)), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 x 10(-103)) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 x 10(-49)), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 x 10(-93)), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 x 10(-23) and OR = 3.39, P = 5.2 x 10(-82), respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk. National Institute for Diabetes and Digestive Kidney Diseases (NIDDK) [RC2-DK116690, R01-DK105124, R01-DK097053, R01-DK108805]; National Institute on Minority Health and Health Disparities (NIMHD)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Minority Health & Health Disparities (NIMHD) [R01-MD009223]; Charles Woodson Clinical Research Fund; Nephrotic Syndrome Study Network Consortium (NEPTUNE) [U54-DK-083912]; Columbia University, Columbia Glomerular Center; Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS); National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK); University of MichiganUniversity of Michigan System; NephCure Kidney International; Halpin Foundation; National Key Research and Development Program of China [2016YFC0904100]; Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81621092]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81870460, 81570598]; Science and Technology Innovation Action Plan of Shanghai Science and Technology Committee [17441902200]; Shanghai Municipal Education Commission, Gaofeng, Clinical Medicine Grant [20152207]; Shanghai Jiao Tong University School of Medicine, Multi-Center Clinical Research Project [DLY201510]; International Cooperation and Exchange Projects of Shanghai Science and Technology Committee [14430721000]; Outstanding Young Scholar Award [81622009]; Shanghai Health and Family Planning Committee Hundred Talents Program [2018BR37]; Seoul National University Hospital Human Biobank, a member of the National Biobank of Korea - Ministry of Health and Welfare, Republic of Korea; MRCMedical Research Council UK (MRC) [MR/J010847/1]; Manchester Academic Health Science Centre [MAHSC 186/200]; Greater Manchester Local Clinical Research Network; Kidneys for Life Charity; David and Elaine Potter Charitable Foundation; St Peter's Trust for Kidney, Bladder and Prostate Research; Kids Kidney Research UKKidney Research UK (KRUK); Kidney Research UKKidney Research UK (KRUK); Italian Ministry of Health grantMinistry of Health, Italy [GR-2011-02350438]; Department of Excellence Grant 2018-2022 - Italian Ministry of Education for the Department of Medical Sciences of the University of Turin; Columbia University; Poznan University of Medical Sciences, Poland; German Ministry of Education and Research (BMBF)Federal Ministry of Education & Research (BMBF) [01ER0804]; KfH Foundation for Preventive Medicine; Bayer Pharma AG; German Research FoundationGerman Research Foundation (DFG) [CRC 1140, KO 3598/3-1, CRC 992]; European Research CouncilEuropean Research Council (ERC) [ERC-2012ADG_2012-0314, 322947]; 7th Framework Programme of the European Community contract [2012-305608]; National Research Agency grant MNaims [ANR-17-CE17-0012-01]; Dutch Kidney Foundation [OW08, KJPB11.021]; National Human Genome Research Institute (NHGRI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI); NIMHD We are grateful to all study participants across multiple nephrology centres worldwide for their contributions to this work. This work was supported by the following institutions, grants and funding agencies in the US: Columbia University, Columbia Glomerular Center, National Institute for Diabetes and Digestive Kidney Diseases (NIDDK) grants RC2-DK116690 (K.K., M.K.), R01-DK105124 (K.K.), R01-DK097053 (L.H.B., M.K.), R01-DK108805 (M.G.S.), and National Institute on Minority Health and Health Disparities (NIMHD) grant R01-MD009223 (K.K., A.G.G., A.B.). M.G.S. is additionally supported by the Charles Woodson Clinical Research Fund. The Nephrotic Syndrome Study Network Consortium (NEPTUNE), U54-DK-083912, is a part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through a collaboration between the Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS) and the National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK). Additional funding and/or programmatic support for this project has also been provided by the University of Michigan, the NephCure Kidney International and the Halpin Foundation. The recruitment and analysis of the Chinese cohorts were supported by the National Key Research and Development Program of China (2016YFC0904100), Natural Science Foundation of China to the Innovation Research Group (81621092), National Natural Science Foundation of China (No. 81870460, 81570598), Science and Technology Innovation Action Plan of Shanghai Science and Technology Committee (No.17441902200), Shanghai Municipal Education Commission, Gaofeng, Clinical Medicine Grant (No.20152207), Shanghai Jiao Tong University School of Medicine, Multi-Center Clinical Research Project (No.DLY201510), International Cooperation and Exchange Projects of Shanghai Science and Technology Committee (No.14430721000), the Outstanding Young Scholar Award for Zhao Cui (No.81622009), and Shanghai Health and Family Planning Committee Hundred Talents Program for Jingyuan Xie (No.2018BR37). The recruitment of the Korean cohort was supported by the Seoul National University Hospital Human Biobank, a member of the National Biobank of Korea, financed by the Ministry of Health and Welfare, Republic of Korea. P.B. and P.H. acknowledge financial support from MRC project "Autoimmunity in Membranous Nephropathy", grant MR/J010847/1 which funded the sample collection from MN patients across the UK. P.B., P.H. and S.H. acknowledge support from Manchester Academic Health Science Centre (MAHSC 186/200), the Greater Manchester Local Clinical Research Network and Kidneys for Life Charity for supporting research in MN in Manchester. We are grateful to the MENTOR study (clinical trials no. NCT01180036), for contributing blood samples of trial participants. The UK cohort was supported in part by grants from the David and Elaine Potter Charitable Foundation (to S.H.P. and R.K.), St Peter's Trust for Kidney, Bladder and Prostate Research (to D.B., H.C.S., S.H.P. and R.K.), Kids Kidney Research UK and Kidney Research UK (to D.B. and R.K.). The Italian cohorts were supported by the Italian Ministry of Health grant GR-2011-02350438 (G.Z., S.G.) and the Department of Excellence Grant 2018-2022 funded by the Italian Ministry of Education for the Department of Medical Sciences of the University of Turin (A.A.).; The recruitment of Polish cases was sponsored by the Polish Kidney Genetics Network (POLYGENES), a collaborative effort between Columbia University and Poznan University of Medical Sciences, Poland. The full list of POLYGENES collaborators can be found in the Supplementary Materials. The GCKD (German Chronic Kidney Disease) study was funded by grants from the German Ministry of Education and Research (BMBF, No. 01ER0804) and the KfH Foundation for Preventive Medicine, with genotyping supported by Bayer Pharma AG. The list of GCKD investigators can be found in the Supplementary Materials. The work of M.W. and A.K. was funded by the CRC 1140 Initiative and by KO 3598/3-1 and CRC 992 (A.K.) of the German Research Foundation. The work of E.H. and R.A.K.S. was funded by the CRC 1192 from the German Research Foundation (Projects B1 and C1). P.R. is a recipient of European Research Council ERC-2012ADG_2012-0314 grant 322947, 7th Framework Programme of the European Community contract 2012-305608 (European Consortium for High-Throughput Research in Rare Kidney Diseases), and the National Research Agency grant MNaims (ANR-17-CE17-0012-01). The Dutch studies were supported by grants from the Dutch Kidney Foundation to JMH and JFW (Nierstichting Nederland grant OW08 and grant KJPB11.021). We would like to thank the Population Architecture Using Genomics and Epidemiology (PAGE) consortium, funded by the National Human Genome Research Institute (NHGRI) with co-funding from the NIMHD, for providing population controls for this study. For full acknowledgment of the PAGE consortium, please see Supplementary Materials. The funding sources were not involved in the study design, collection, analysis, and interpretation of data, writing of the report, or in the decision to submit the paper for publication.

Pancreatic cancer decreases survival time and quality of life because of drug resistance and peripheral neuropathy during conventional treatment. This study was undertaken to investigate whether alpha v beta 3 integrin receptor antagonist compounds NDAT and XT199 can suppress the development of cisplatin resistance and cisplatin-induced peripheral neuropathy in an orthotopic pancreatic SUIT2-luc cancer cell mouse model. Anticancer effects of these compounds and their combination with cisplatin were assessed in this tumor mouse model with bioluminescent signaling and histopathology, and a cytokine assay was used to examine expression of inflammatory cytokines IL-1 beta, IL-6, IL-10, and TNF-alpha from plasma samples. To determine the neuroprotective effects of the compounds on cisplatin-induced peripheral neuropathy, behavioral hind-limb posture of the mice was evaluated. The combination therapy of NDAT or XT199 with cisplatin elicited greater inhibition of tumor growth and increased tumor necrosis compared to cisplatin alone. NDAT and XT199 in combination with cisplatin significantly decreased expression of pro-inflammatory cytokines IL-1 beta, IL-6, and TNF-alpha and significantly increased expression of anti-inflammatory cytokine IL-10 in comparison to cisplatin alone. Cisplatin-treated groups showed stocking-glove hind-limb posture, whereas NDAT and XT199 with cisplatin-treated groups displayed normal hind-limb posture. Results clearly suggest that NDAT and XT199 treatment with cisplatin that inactivates NF-kappa B may contribute to increased antitumor and anti-inflammatory efficacy as well as alleviate cisplatin-mediated loss of motor function in this pancreatic tumor mouse model. Pharmaceutical Research Institute at Albany College of Pharmacy Health and Sciences

Atherosclerosis is an inflammatory disease characterized by the accumulation of macrophages in the vessel wall. Macrophages depend on their polarization to exert either pro-inflammatory or anti-inflammatory effects. Macrophages of the anti-inflammatory phenotype express high levels of CD163, a scavenger receptor for the hemoglobin-haptoglobin complex. CD163 can also bind to the pro-inflammatory cytokine TWEAK. Using ApoE-deficient or ApoE/CD163 double-deficient mice we aim to investigate the involvement of CD163 in atherosclerosis development and its capacity to neutralize the TWEAK actions. ApoE/CD163 double-deficient mice displayed a more unstable plaque phenotype characterized by an increased lipid and macrophage content, plaque size, and pro-inflammatory cytokine expression. In vitro experiments demonstrated that the absence of CD163 in M2-type macrophages-induced foam cell formation through upregulation of CD36 expression. Moreover, exogenous TWEAK administration increased atherosclerotic lesion size, lipids, and macrophages content in ApoE-/-/CD163-/- compared with ApoE-/-/CD163+/+ mice. Treatment with recombinant CD163 was able to neutralize the proatherogenic effects of TWEAK in ApoE/CD163 double-deficient mice. Recombinant CD163 abolished the pro-inflammatory actions of TWEAK on vascular smooth muscle cells, decreasing NF-kB activation, cytokines and metalloproteinases expression, and macrophages migration. In conclusion, CD163-expressing macrophages serve as a protective mechanism to prevent the deleterious effects of TWEAK on atherosclerotic plaque development and progression. © 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology

Interleukin (IL)-6 is an important mediator of neurovascular dysfunction, neurodegeneration and/or neuroinflammation. We previously reported that brain pericytes released higher levels of IL-6 than did glial cells (astrocytes and microglia) in response to tumor necrosis factor (TNF)-?. Moreover, pericytes stimulated with TNF-? enhanced activation of BV-2 microglia. In this study, we investigated the mechanisms of TNF-? mediated induction of IL-6 release from brain pericytes and astrocytes and whether pericyte-derived IL-6 would facilitate activation of BV-2 microglia. Using rat brain pericyte and astrocyte primary cultures and pharmacological inhibitors, we found that, TNF-? induced the highest levels of IL-6 release from pericytes by activating the inhibitor kappa B (I?B)-nuclear factor kappa-light-chain-enhancer of activated B cells (NF?B) and Janus family of tyrosine kinase (JAK)-signal transducer and activator of transcription (STAT)3 pathways. STAT3 contributed to TNF-? induced nuclear translocation of phospho-NF?B in pericytes. TNF-?-induced IL-6 release in astrocytes was mediated by NF?B but not by STAT3. The presence of pericytes amplified TNF-?-induced iNOS mRNA expression in BV-2 microglia. This effect was blocked by a neutralizing antibody for IL-6. These findings indicated that crosstalk between the I?B-NF?B and JAK-STAT3 pathways is a pericyte specific mechanism, not occurring in astrocytes, for TNF-?-induced IL-6 release. IL-6 derived from pericytes enhanced microglial activation. Our findings increase understanding of the role of pericyte-microglia crosstalk in the brain under neuroinflammatory conditions and suggest a potentially attractive therapeutic target for brain inflammation. © 2018 Elsevier B.V.

Nerve injury provokes microglial activation, contributing to the sensory and emotional disorders associated with neuropathic pain that do not completely resolve with treatment. In C57BL/6J mice with neuropathic pain induced by chronic constriction of the sciatic nerve (CCI), we evaluated the effects of oltipraz, an antioxidant and anticancer compound, on (1) allodynia and hyperalgesia, (2) microglial activation and pain signaling pathways, (3) oxidative stress, and (4) depressive-like behaviors. Twenty-eight days after surgery, we assessed the effects of oltipraz on the expression of CD11b/c (a microglial marker), phosphoinositide 3-kinase (PI3K)/ phosphorylated protein kinase B (p-Akt), nuclear factor-?B (NF-?B) transcription factor, and mitogen activated protein kinases (MAPK) in the spinal cord, hippocampus, and prefrontal cortex. Our results show that oltipraz alleviates neuropathic pain by inhibiting microglial activation and PI3K/p-Akt, phosphorylated inhibitor of ?Ba (p-I?Ba), and MAPK overexpression, and by normalizing and/or enhancing the expression of antioxidant proteins, nuclear factor erythroid derived-2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), and NAD(P)H:quinone oxidoreductase-1 (NQO1) in the spinal cord. The inhibition of microglial activation and induction of the Nrf2/HO-1/NQO1 signaling pathway in the hippocampus and/or prefrontal cortex may explain the antidepressant effects of oltipraz during neuropathic pain. These data demonstrate the analgesic and antidepressant effects of oltipraz and reveal its protective and antioxidant properties during chronic pain. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

Atherothrombosis is the principal underlying cause of cardiovascular disease (CVD). Microvesicles (MV) are small blebs originated by an outward budding at the cell plasma membranes, which are released in normal conditions. However, MV release is increased in pathophysiologic conditions such as CVD. Low density lipoprotein (LDL) and MV contribute to atherothrombosis onset and progression by promoting inflammation and leukocyte recruitment to injured endothelium, as well as by increasing thrombosis and plaque vulnerability. Moreover, (oxidized)LDL induces MV release and vice-versa, perpetuating endothelium injury leading to CVD progression. Therefore, MV and lipoproteins exhibit common features, which should be considered in the interpretation of their respective roles in the pathophysiology of CVD. Understanding the pathways implicated in this process will aid in developing novel therapeutic approaches against atherothrombosis. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.

Background:Non-Small Cell Lung Cancer (NSCLC) is an aggressive cancer type due to high metastatic capacity. Nuclear Factor Kappa B (NF-κB) is a consistently active transcription factor in malignant lung cancer cells and has crucial significance in NSCLC progression. It is also implicated in the transcriptional regulation of many genes including microRNAs (miRNAs) that function as tumor suppressor or oncogene. It has been increasingly reported that several miRNAs defined as gene members are induced by NF-κB. The present study aimed to find novel miRNAs that are regulated by NF-κB.Methods:Chromatin İmmunoprecipitation Sequencing (ChIP-Seq) experiment and bioinformatic analysis were used to determine NF-κB-dependent miRNAs. Western blot analysis, quantitative real-time polymerase chain reaction (qRT-PCR), luciferase reporter gene assays were carried out to investigate the target genes of miRNAs. To determine biologic activity, transwell invasion and MTT assay were carried out on H1299 NSCLC cell line. miRNA expression level was evaluated in metastatic and non-metastatic tissue samples of NSCLC patients.Results:ChIP-Seq and qRT-PCR experiments showed that miR-548as-3p is transcriptionally regulated by NF- κB in response to Tumor Necrosis Factor-α (TNF-α) treatment. Then, we found that tumor suppressor Phosphatase and Tension homolog (PTEN) is a direct target of miR-548as-3p. Furthermore, miR-548as-3p mediates phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway and NF-κB-implicated genes including Matrix Metalloproteinases 9 (MMP9), Slug and Zeb1. We further showed that miR-548as-3p increased invasiveness of NSCLC cells and was upregulated in metastatic tumor tissues compared to non-metastatic ones.Conclusion:All these findings provide a miRNAs-mediated novel mechanism for NF-κB signaling and that miR-548as-3p could be a biomarker for NSCLC metastasis.

Lambda interferons (IFNλs, type III IFNs or interleukins-28/29) were described fifteen years ago as novel cytokines sharing structural and functional homology with IL-10 and type I IFNs, respectively. IFNλs engage a unique receptor complex comprising IFNLR1 and IL10R2, nevertheless they share signaling cascade and many functions with type I IFNs, questioning their possible non-redundant roles and overall biological importance. Here, we review the latest evidence establishing the primacy of IFNλs in front line protection at anatomical barriers, mediating antiviral immunity before type I IFNs. We also discuss their emerging role in regulating inflammation and limiting host damage, a major difference to type I IFNs. IFNλs come thus to light as dual function cytokines mediating antiviral immunity and damage control.

Constitutive Wnt signaling promotes intestinal cell proliferation, but signals from the tumor microenvironment are also required to support cancer development. The role that signaling proteins play to establish a tumor microenvironment has not been extensively studied. Therefore, we assessed the role of the proinflammatory Ikk-related kinase Ikkϵ in Wnt-driven tumor development. We found that Ikkϵ was activated in intestinal tumors forming upon loss of the tumor suppressor Apc. Genetic ablation of Ikkϵ in β-catenin-driven models of intestinal cancer reduced tumor incidence and consequently extended survival. Mechanistically, we attributed the tumor-promoting effects of Ikkϵ to limited TNF-dependent apoptosis in transformed intestinal epithelial cells. In addition, Ikkϵ was also required for lipopolysaccharide (LPS) and IL17A-induced activation of Akt, Mek1/2, Erk1/2, and Msk1. Accordingly, genes encoding pro-inflammatory cytokines, chemokines, and anti-microbial peptides were downregulated in Ikkϵ-deficient tissues, subsequently affecting the recruitment of tumor-associated macrophages and IL17A synthesis. Further studies revealed that IL17A synergized with commensal bacteria to trigger Ikkϵ phosphorylation in transformed intestinal epithelial cells, establishing a positive feedback loop to support tumor development. Therefore, TNF, LPS, and IL17A-dependent signaling pathways converge on Ikkϵ to promote cell survival and to establish an inflammatory tumor microenvironment in the intestine upon constitutive Wnt activation. Cancer Res; 76(9); 2587–99. ©2016 AACR.

In our study, the effect of hesperetin on inflammatory and oxidative status in trinitrobenzene sulfonic acid (TNBS)-induced experimental colitis model was investigated through different methods. Eighteen Wistar albino male rats were divided in to three groups: Group I (Control, n = 8; 1 ml physiological saline), Group II (Colitis, n = 8; 1 ml TNBS), Group III (Hesperetin, n = 8; 1 ml TNBS and 100 mg/kg hesperetin). Macroscopic and microscopic scores were calculated to determine the damage to the colon at the end of the experiment. Serum tumor necrosis factor-? (TNF-?) and tissue interleukin-6 (IL-6) levels were determined using the ELISA method. Myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA) levels were investigated spectrophotometrically. The TUNEL method was used for the detection of apoptotic cells in the colon tissue. Inducible nitric oxide synthase (iNOS) and nuclear factor-kappa-B (NF-??) expression in the colon were determined immunohistochemically. Hesperetin administration has shown to significantly reduce levels of MPO, MDA, and proinflammatory agents (TNF-?, IL-6, and NF-??). It has also been proven to inhibit mucosal apoptosis. This study indicates that hesperetin is protective against TNBS-induced colitis model via antiinflammatory, antioxidant and antiapoptotic effects. © 2018 by the C.M.B. Association. All rights reserved. We acknowledge Scientific Research Project Department of Namık Kemal University for the grant given under project code NKUBAP.02.GA.17.085.

Familial hypercholesterolemia (FH) conveys a high risk of premature atherosclerosis as a result of lifelong exposure to high LDL cholesterol levels that are not fully reduced by standard-of-care lipid-lowering treatment. Inflammatory mediators have played a role in the progression of atherosclerotic lesions. Here, we investigated whether innate immunity cells in patients with FH have a specific proinflammatory phenotype that is distinct from that of cells in normal participants. To this end, miR-505-3p-a microRNA related to chronic inflammation-and its target genes were investigated in monocyte-derived macrophages (MACs) of patients with FH (FH-MACs) and non-FH controls (co-MACs). On the basis of the profiler PCR array analysis of agomiR-505-3p-transfected MACs, we identified the chemokine receptors, CCR3, CCR4, and CXCR1, as genes that are regulated by miR-505-3p via the transcription factor, RUNX1. miR-505-3p was significantly down-regulated, whereas CCR3, CCR4, CXCR, and RUNX1 were increased in FH-MAC compared with co-MAC, with the increase being more evident in the proinflammatory M1-like FH-MAC. Chemokine receptor levels were unrelated to LDL plasma levels at entry, but correlated with age in patients with FH, not in controls. In summary, we demonstrate for first time to our knowledge that MACs from FH-MACs have an inflammatory phenotype that is characterized by the up-regulation of CCR3, CCR4, and CXCR1 under the control of miR-505-3p. These results suggest a chronic inflammatory condition in FH innate immunity cells that is not reverted by standard lipid-lowering treatment.-Escate, R., Mata, P., Cepeda, J. M., Padr, T., Badimon, L. miR-505-3p controls chemokine receptor up-regulation in macrophages: role in familial hypercholesterolemia.

Constitutively activated prosurvival pathways render cancer cells addicted to their effects. Consequently they turn out to be the Achilles’ heels whose inhibition can be exploited in anticancer therapy. Primary effusion lymphomas (PELs) are very aggressive non-Hodgkin’s B cell lymphomas, whose pathogenesis is strictly linked to Kaposi’s sarcoma herpesvirus (KSHV) infection. Here we summarized previous studies from our and other laboratories exploring the cytotoxic effect of drugs inhibiting the main prosurvival pathways activated in PEL cells. Moreover, the immunogenicity of cell death, in terms of dendritic cell (DC) activation and their potential side effect on DCs, is discussed.

Inflammation is a central feature of liver fibrosis as suggested by its role in the activation of hepatic stellate cells leading to extracellular matrix deposition. During liver injury, inflammatory cells are recruited in the injurious site through chemokines attraction. Thus, inflammation could be a target to reduce liver fibrosis. The pandemic trend of obesity, combined with the high incidence of alcohol intake and viral hepatitis infections, highlights the urgent need to find accessible antifibrotic therapies. Medicinal plants are achieving popularity as antifibrotic agents, supported by their safety, cost-effectiveness, and versatility. The aim of this review is to describe the role of inflammation and the immune response in the pathogenesis of liver fibrosis and detail the mechanisms of inhibition of both events by medicinal plants in order to reduce liver fibrosis. Copyright © 2015 Florent Duval et al.

Purpose: Aldo-keto reductases (including AKR1B1 and AKR1B10) constitute a family of oxidoreductases that have been implicated in the pathophysiology of diabetes and cancer, including colorectal cancer (CRC). Available data indicate that, despite their similarities in structure and enzymatic functions, their roles in CRC may be divergent. Here, we aimed to determine the expression and functional implications of AKR1B1 and AKR1B10 in CRC. Methods: AKR1B1 and AKR1B10 gene expression levels were analyzed using publicly available microarray data and ex vivo CRC-derived cDNA samples. Gene Set Enrichment Analysis (GSEA), The Cancer Genome Atlas (TCGA) RNA-seq data and The Cancer Proteome Atlas (TCPA) proteome data were analyzed to determine the effect of high and low AKR1B1 and AKR1B10 expression levels in CRC patients. Proliferation, cell cycle progression, cellular motility, adhesion and inflammation were determined in CRC-derived cell lines in which these genes were either exogenously overexpressed or silenced. Results: We found that the expression of AKR1B1 was unaltered, whereas that of AKR1B10 was decreased in primary CRCs. GSEA revealed that, while high AKR1B1 expression was associated with increased cell cycle progression, cellular motility and inflammation, high AKR1B10 expression was associated with a weak inflammatory phenotype. Functional studies carried out in CRC-derived cell lines confirmed these data. Microarray data analysis indicated that high expression levels of AKR1B1 and AKR1B10 were significantly associated with shorter and longer disease-free survival rates, respectively. A combined gene expression signature of AKR1B10 (low) and AKR1B1 (high) showed a better prognostic stratification of CRC patients independent of confounding factors. Conclusions: Despite their similarities, the expression levels and functions of AKR1B1 and AKR1B10 are highly divergent in CRC, and they may have prognostic implications.

Major Depressive Disorder (MDD) is common among cancer patients, with prevalence rates up to four-times higher than the general population. Depression confers worse outcomes, including non-adherence to treatment and increased mortality in the oncology setting. Advances in the understanding of neurobiological underpinnings of depression have revealed shared biobehavioral mechanisms may contribute to cancer progression. Moreover, psychosocial stressors in cancer promote: (1) inflammation and oxidative/nitrosative stress; (2) a decreased immunosurveillance; and (3) a dysfunctional activation of the autonomic nervous system and of the hypothalamic–pituitaryadrenal axis. Consequently, the prompt recognition of depression among patients with cancer who may benefit of treatment strategies targeting depressive symptoms, cognitive dysfunction, fatigue and sleep disturbances, is a public health priority. Moreover, behavioral strategies aiming at reducing psychological distress and depressive symptoms, including addressing unhealthy diet and life-style choices, as well as physical inactivity and sleep dysfunction, may represent important strategies not only to treat depression, but also to improve wider cancer-related outcomes. Herein, we provide a comprehensive review of the intertwined biobehavioral pathways linking depression to cancer progression. In addition, the clinical implications of these findings are critically reviewed. © 2016 Elsevier Ltd 52 58 70

Background: Bronchopulmonary dysplasia (BPD) is a chronic lung disease that causes significant morbidity and mortality in premature infants. Inflammation and oxidative injury play an important role in the pathogenesis of BPD. Resveratrol is an antioxidant and anti-inflammatory agent. In this study, the histopathological and biochemical effects of resveratrol on a hyperoxia-induced lung injury model in newborn rats were investigated., Methods: The experiment was performed on newborn rat pups from the 3rd to 13th postnatal day and they were randomly divided into four groups: Group 1 (air-exposed + saline, n Z 10), Group 2 (air-exposed + resveratrol, n Z 11), Group 3 (hyperoxia-exposed + saline, n Z 6) and Group 4 (hyperoxia-exposed + resveratrol, n Z 7). Resveratrol was administered (30 mg/kg/day) intraperitoneally. The histopathological effects of resveratrol on lung tissue were assessed by alveolar surface area, fibrosis, and smooth muscle actin (SMA) score, and the biochemical effects on lung tissue were assessed by glutathione (GSH), superoxide dismutase (SOD), nitric oxide (NO), tumor necrosis factor-? (TNF-?), and nuclear factor kappa B (NF-?B) levels., Results: The alveolar surface area, fibrosis, SMA score, and NO levels were found to be significantly higher in Group 3 compared with Group 1 (p < 0.05). In addition, it was found that resveratrol treatment significantly reduced the SMA score and the NO and TNF-? levels, and increased the GSH and SOD levels in the hyperoxia group (p < 0.05)., Conclusion: This experimental study showed that oxidative stress and NO contributed to the pathogenesis of hyperoxia-induced lung injury, and that resveratrol had a preventive effect on hyperoxic lung injury through its anti-inflammatory and antioxidant properties. © 2014, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.

Several epidemiological studies have shown that the consumption of finger millet (FM) alleviates diabetes-related complications. In the present study, the effect of finger millet whole grain (FM-WG) and bran (FM-BR) supplementation was evaluated in high-fat diet-fed LACA mice for 12 weeks. Mice were divided into four groups: control group fed a normal diet (10 % fat as energy); a group fed a high-fat diet; a group fed the same high-fat diet supplemented with FM-BR; a group fed the same high-fat diet supplemented with FM-WG. The inclusion of FM-BR at 10 % (w/w) in a high-fat diet had more beneficial effects than that of FM-WG. FM-BR supplementation prevented body weight gain, improved lipid profile and anti-inflammatory status, alleviated oxidative stress, regulated the expression levels of several obesity-related genes, increased the abundance of beneficial gut bacteria (Lactobacillus, Bifidobacteria and Roseburia) and suppressed the abundance of Enterobacter in caecal contents (P≤ 0·05). In conclusion, FM-BR supplementation could be an effective strategy for preventing high-fat diet-induced changes and developing FM-BR-enriched functional foods.

Integrin alpha M(ITGAM; CD11b) is a component of the macrophage-1 antigen complex, which mediates leukocyte adhesion, migration and phagocytosis as part of the immune system.We previously identified amissense polymorphism, rs1143679 (R77H), strongly associated with systemic lupus erythematosus (SLE). However, the molecularmechanismsof this variant are incompletely understood. Ameta-analysis of publishedandnovel data on 28 439 individuals with European, African, Hispanic and Asian ancestries reinforces genetic association between rs1143679 and SLE [Pmeta = 3.60 × 10-90, odds ratio (OR) 5 1.76]. Since rs1143679 is in the most active region of chromatin regulation and transcription factor binding in ITGAM, we quantitated ITGAM RNA and surface protein levels inmonocytes from patients with each rs1143679 genotype.Weobserved that transcript levels significantly decreased for the risk allele ('A') relative to the non-risk allele ('G'), in a dose-dependent fashion: ('AA' and lt; 'AG' and lt; 'GG'). CD11b protein levels in patients' monocytes were directly correlated with RNA levels. Strikingly, heterozygous individuals express much lower (average 10-to 15-fold reduction) amounts of the 'A' transcript than 'G' transcript. Wefound that the non-risk sequence surrounding rs1143679 exhibits transcriptional enhancer activity in vivo and binds to Ku70/80, NFKB1 and EBF1 in vitro, functions that are significantly reduced with the risk allele. Mutant CD11b protein shows significantly reduced binding to fibrinogen and vitronectin, relative to non-risk, both in purified protein and in cellular models. This two-pronged contribution (nucleic acid-and protein-level) of the rs1143679 risk allele to decreasing ITGAM activity provides insight into the molecular mechanisms of its potent association with SLE. © The Author 2014. Published by Oxford University Press. All rights reserved.

Although the transcript level of inducible heat shock protein 70.3 (Hsp70.3, also known as Hspa1a) is altered in various disease states, its transcriptional regulation remains incompletely understood. Here, we systematically analyzed the Hspa1a promoter to identify major cis elements and transcription factors that may govern the constitutive/inducible gene expression. Computational analyses coupled with extensive in vitro (promoter-reporter activity and electrophoretic mobility shift assays) and in vivo (chromatin immunoprecipitation assays) revealed interaction of several transcription factors with Hspa1a promoter motifs: HSF-1 (heat shock factor 1) at - 114/- 97 bp and - 788/- 777 bp, NF-Y (nuclear transcription factor Y) at - 73/- 58 bp, NF-?B (nuclear factor kappa B) at - 133/- 124 bp, and CREB (cAMP response element binding protein) at - 483/- 476 bp. Consistently, siRNA (small interfering RNA)-mediated down-regulation of each of these transcription factors caused substantial reduction of endogenous Hspa1a expression. Heat-shock-induced activation of Hspa1a was coordinately regulated by HSF-1 and NF-Y/NF-?B. The Hspa1a expression was augmented by TNF-? (tumor necrosis factor-alpha) and forskolin in NF-?B and CREB-dependent manners, respectively. NF-?B and CREB also activated Hspa1a transcription in cardiac myoblasts upon exposure to ischemia-like conditions. Taken together, this study discovered previously unknown roles for NF-?B and CREB to regulate Hspa1a expression and a coordinated action by several transcription factors for Hspa1a transactivation under heat-shock/ischemia-like conditions and thereby provided new insights into the mechanism of Hspa1a regulation. � 2013 Elsevier Ltd.

Prostate cancer is worldwide the sixth leading cause of cancer related death in men thus early detection and successful treatment are still of major interest. The commonly performed screening of the prostate-specific antigen (PSA) is controversially discussed, as in many patients the prostate-specific antigen levels are chronically elevated in the absence of cancer. Due to the unsatisfying efficiency of available prostate cancer screening markers and the current treatment outcome of the aggressive hormone refractory prostate cancer, the evaluation of novel molecular markers and targets is considered an issue of high importance. MicroRNAs are relatively stable in body fluids orchestrating simultaneously the expression of many genes. These molecules are currently discussed to bear a greater diagnostic potential than protein-coding genes, being additionally promising therapeutic drugs and/or targets. Herein we review the potential impact of the microRNAlet-7family on prostate cancer and show how deregulation of several of its target genes could influence the cellular equilibrium in the prostate gland, promoting cancer development as they do in a variety of other human malignant neoplasias.

The genetic factors underlying the pathogenesis of lupus nephritis associated with systemic lupus erythematosus are largely unknown, although animal studies indicate that nuclear factor (NF)-?B is involved. We reported previously that aknockin mouse expressinganin active form of ABIN1 (ABIN1[D485N]) develops lupus-like autoimmune disease and demonstrates enhanced activation of NF-?B and mitogen-activated protein kinases in immune cells after toll-like receptor stimulation. In the current study, we show that ABIN1[D485N] mice develop progressive GN similar to class III and IV lupus nephritis in humans. To investigate the clinical relevance of ABIN1 dysfunction, we genotyped five single-nucleotide polymorphisms in the gene encoding ABIN1, TNIP1, in samples from European-American, African American, Asian, Gullah, and Hispanic participants in the Large Lupus Association Study 2. Comparing cases of systemic lupus erythematosus with nephritis and cases ofsystemic lupus erythematosus without nephritis revealed strong associations with lupus nephritis at rs7708392 in European Americans and rs4958881 in African Americans. Comparing cases of systemic lupus erythematosus with nephritis and healthy controls revealed a stronger association at rs7708392 in European Americans but not at rs4958881 in African Americans. Our data suggest that variants in the TNIP1 gene are associated with the risk for lupus nephritis and could be mechanistically involved in disease development via aberrant regulation of NF-?B and mitogen-activated protein kinase activity. Copyright © 2013 by the American Society of Nephrology.

MicroRNAs (miRNAs) are 20-22-nucleotide small endogenous non-coding RNAs which regulate gene expression at post-transcriptional level. In the last two decades, identification of almost 2600 miRNAs in human and their potential to be modulated opened a new avenue to target almost all hallmarks of cancer. miRNAs have been classified as tumor suppressors or oncogenes depending on the phenotype they induce, the targets they modulate, and the tissue where they function. miR-200c, an illustrious tumor suppressor, is one of the highly studied miRNAs in terms of development, stemness, proliferation, epithelial-mesenchymal transition (EMT), therapy resistance, and metastasis. In this review, we first focus on the regulation of miR-200c expression and its role in regulating EMT in a ZEB1/E-cadherin axis-dependent and ZEB1/E-cadherin axis-independent manner. We then describe the role of miR-200c in therapy resistance in terms of multidrug resistance, chemoresistance, targeted therapy resistance, and radiotherapy resistance in various cancer types. We highlight the importance of miR-200c at the intersection of EMT and chemoresistance. Furthermore, we show how miR-200c coordinates several important signaling cascades such as TGF-beta signaling, PI3K/Akt signaling, Notch signaling, VEGF signaling, and NF-kappa B signaling. Finally, we discuss miR-200c as a potential prognostic/diagnostic biomarker in several diseases, but mainly focusing on cancer and its potential application in future therapeutics.

Objectives Metastasis-associated antigen 1 (MTA1) is implicated in metastasis while 15-lipoxygenase-1 (15-LOX-1) reduces cell motility, when re-expressed in colorectal cancer (CRC). We aimed to understand any potential interplay between MTA1 and 15-LOX-1 in CRC metastasis. Materials and methods ALOX15 and MTA1 expression in tumour and normal samples were analysed from TCGA RNA-seq data, microarray data sets and a human CRC cDNA array. Western blots, chromatin immunoprecipitation (ChIP), luciferase assays and electrophoretic mobility shift assays (EMSA) were carried out in HT-29 and LoVo cells re-expressing 15-LOX-1 to determine NF- κB activity at the MTA1 promoter. Functional assays in cells ectopically expressing either 15-LOX-1, MTA-1 or both, were carried out to determine adhesion and cell motility. Results Significantly higher expression of MTA1 was observed in tumours compared to normal tissues; MTA1 overexpression resulted in reduced adhesion in CRC cell lines. Re-expression of 15-LOX-1 in the CRC cell lines reduced expression of endogenous MTA1, corroborated by negative correlation between the two genes in two independent human CRC microarray data sets, with greater significance in specific subsets of patients. DNA binding and transcriptional activity of NF-κB at the MTA1 promoter was significantly lower in cells re-expressing 15-LOX-1. Functionally, the same cells had reduced motility, which was rescued when they overexpressed MTA1, and further corroborated by expressions of E-cadherin and vimentin. Conclusions Expression of MTA1 and 15-LOX-1 negatively correlated in specific subsets of CRC. Mechanistically, this is at least in part through reduced recruitment of NF-κB to the MTA1 promoter.

Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor that affects older people. Although the current therapeutic approaches for GBM include surgical resection, radiotherapy, and chemotherapeutic agent temozolomide, the median survival of patients is 14.6 months because of its aggressiveness. Zoledronic acid (ZA) is a nitrogen-containing bisphosphonate that exhibited anticancer activity in different cancers. The purpose of this study was to assess the potential effect of ZA in distinct signal transduction pathways in U87-MG cells. In this study, experiments performed on U87-MG cell line (Human glioblastoma-astrocytoma, epithelial-like cell line) which is an in vitro model of human glioblastoma cells to examine the cytotoxic and apoptotic effects of ZA. IC50 dose of ZA, 25 μM, applied on U87-MG cells during 72 h. ApoDIRECT In Situ DNA Fragmentation Assay was used to investigate apoptosis of U87MG cells. The quantitative reverse transcription polymerase chain reaction (qRT-PCR) (LightCycler480 System) was carried out for 48 gene expression like NF-κB, Toll-like receptors, cytokines, and inteferons. Our results indicated that ZA (IC50 dose) increased apoptosis 1.27-fold in U87MG cells according to control cells. According to qRT-PCR data, expression levels of the endoplasmic reticulum-nuclei-1 (ERN1), Toll-like receptor 2 (TLR2), and human IFN regulatory factor 5 (IRF5) tumor suppressor genes elevated 2.05-, 2.08-, and 2.3-fold by ZA, respectively, in U87MG cells. Our recent results indicated that ZA have a key role in GBM progression and might be considered as a potential agent in glioma treatment. © 2015, International Society of Oncology and BioMarkers (ISOBM).

Since ancient times, Capparis species have been widely used in traditional medicine to treat various diseases. Our recent investigations have suggested Capparis ovata-s potential anti-neuroinflammatory application for the treatment of multiple sclerosis (MS). The present study was designed to precisely determine the underlying mechanism of its anti-neuroinflammatory effect in a mouse model of MS. C. ovata water extract (COWE) was prepared using the plant-s fruit, buds, and flower parts (Turkish Patent Institute, PT 2012/04,093). We immunized female C57BL/6 J mice with MOG(35_55)/CFA. COWE was administered at a daily dose of 500 mg/Kg by oral gavage either from the day of immunization (T1) or at disease onset (12) for 21 days. Gene expression analysis was performed using a Mouse Multiple Sclerosis RT2 Profiler PCR Array, and further determinations and validations of the identified genes were performed using qPCR. Whole-genome transcriptome profiling was analyzed using Agilent SurePrint G3 Mouse GE 8X60K microarrays. Immunohistochemical staining was applied to brain sections of the control and treated mice to examine the degree of degeneration. COWE was further fractionated and analyzed phytochemically using the Zivak Tandem Gold Triple Quadrupole LC/MS-MS system. COWE remarkably suppressed the development of EAE in T1, and the disease activity was completely inhibited. In the T2 group, the maximal score was significantly reduced compared with that of the parallel EAE group. The COWE suppression of EAE was associated with a significantly decreased expression of genes that are important in inflammatory signaling, such as TNF alpha, IL6, NF-kappa B, CCL5, CXCL9, and CXCK10. On the other hand, the expression of genes involved in myelination/remyelination was significantly increased. Immunohistochemical analysis further supported these effects, showing that the number of infiltrating immune cells was decreased in the brains of COWE-treated animals. In addition, differential expression profiling of the transcriptome revealed that COWE treatment caused the down regulation of a group of genes involved in the immune response, inflammatory response, antigen processing and presentation, B-cell-mediated immunity and innate immune response. Collectively, these results suggest anti-neuroinflammatory mechanisms by which COWE treatment delayed and suppressed the development of EAE and ameliorated the disease in mice with persistent clinical signs. (C) 2016 Elsevier B.V. All rights reserved. Türkiye Bilimsel Ve Teknolojik Araştırma Kurumu ( Tübitak )

Autoimmune diseases (ADs) represent a heterogeneous group of disorders that affect specific target organs or multiple organ systems. These conditions share common immunopathogenic mechanisms (i.e., the autoimmune tautology), which explain the clinical similarities they have among them as well as their familial clustering (i.e., coaggregation). As part of the autoimmune tautology, the influence of environmental exposure on the risk of developing ADs is paramount (i.e., the autoimmune ecology). In fact, environment, more than genetics, shapes immune system. Autoimmune ecology is akin to exposome, that is all the exposures - internal and external - across the lifespan, interacting with hereditary factors (both genetics and epigenetics) to favor or protect against autoimmunity and its outcomes. Herein, we provide an overview of the autoimmune ecology, focusing on the immune response to environmental agents in general, and microbiota, cigarette smoking, alcohol and coffee consumption, socioeconomic status (SES), gender and sex hormones, vitamin D, organic solvents, and vaccines in particular. Inclusion of the autoimmune ecology in disease etiology and health will improve the way personalized medicine is currently conceived and applied. © 2016 Anaya, Ramirez-Santana, Alzate, Molano-Gonzalez and Rojas-Villarraga.

Nuclear factor kappa B (NF-?B), an oncogenic signaling factor plays a critical role in the development and progression of various cancers. The objective of this study was to investigate the effect of nimbolide, a neem derived tetranortriterpenoid on NF-?B signaling and its downstream events - Wnt/?-catenin activation and apoptosis evasion in human hepatocarcinoma (HepG2) cells by evaluating NF-?B family members (NF-?B-p50, p65, I?B-?, p-I?B-?, and IKK?), members of Wnt signaling (GSK-3? and ?-catenin), and intrinsic apoptosis (Bcl-2, Bax, cytochrome c, Smac/DIABLO, caspase-3, and caspase-9). Our results demonstrate that nimbolide concurrently abrogates canonical NF-?B and Wnt signaling and induces intrinsic apoptosis in HepG2 cells. These data suggest that phytochemicals such as nimbolide that can target multiple steps along the NF-?B signaling circuit are promising candidates for future phytochemical-based mechanistic pathway targeted anticancer regimens. � 2012 Elsevier B.V. All rights reserved.

Limonoids from the neem tree (Azadirachta indica) have attracted considerable research attention in recent years owing to their potent antioxidant and anti-proliferative effects. The present study was designed to investigate the cellular and molecular mechanisms by which azadirachtin and nimbolide exert cytotoxic effects in the human cervical cancer (HeLa) cell line. Both azadirachtin and nimbolide significantly suppressed the viability of HeLa cells in a dose-dependent manner by inducing cell cycle arrest at G0/G1 phase accompanied by p53-dependent p21 accumulation and down-regulation of the cell cycle regulatory proteins cyclin B, cyclin D1 and PCNA. Characteristic changes in nuclear morphology, presence of a subdiploid peak and annexin-V staining pointed to apoptosis as the mode of cell death. Increased generation of reactive oxygen species with decline in the mitochondrial transmembrane potential and release of cytochrome c confirmed that the neem limonoids transduced the apoptotic signal via the mitochondrial pathway. Altered expression of the Bcl-2 family of proteins, inhibition of NF-?B activation and over-expression of caspases and survivin provide compelling evidence that azadirachtin and nimbolide induce a shift of balance toward a pro-apoptotic phenotype. Antioxidants such as azadirachtin and nimbolide that can simultaneously arrest the cell cycle and target multiple molecules involved in mitochondrial apoptosis offer immense potential as anti-cancer therapeutic drugs. � 2010 Informa UK Ltd.

Chemokine receptors are essential mediators of the metastatic spread in various cancer types; however their precise function in the development of secondary tumors remains poorly understood. We report here a novel property of the chemokine receptors CXCR4 and CCR7 in inhibiting detachment-induced cell death - anoikis, which is believed to be one of the major blocks in the metastatic spread of various neoplasms. Activation of these chemokine receptors by their respective ligands, CXCL12 and CCL21 specifically reduced the sensitivity of metastatic breast cancer cells to anoikis by a distinct mechanism of selective regulation of pro-apoptotic Bmf and anti-apoptotic Bcl-xL proteins. Consequently, functional CXCR4 and CCR7 increased cell survival in the absence of correct ECM attachment both in vitro and in vivo. We also demonstrated that preventing chemokine-induced reduction in Bmf levels significantly attenuated breast cancer metastasis in an experimental mouse model. These results provide evidence for a previously unknown axis in malignant tumors, which connects chemokine receptors with deregulated apoptosis in the absence of the appropriate cell - ECM interaction and may offer novel targets for therapeutic intervention for the treatment of metastatic breast and potentially other tumors. Refereed/Peer-reviewed

The UV-inactivated herpes simplex virus 1 (HSV-1) and glycoprotein D (gD) of HSV-1 have been shown to activate nuclear factor kappaB (NF-kappaB) in U937 cells, but mechanisms involved in this activation have not been elucidated. Here we report that: (i) UV-inactivated HSV-1 induced an increased NF-kappaB activation in cells expressing human HVEM (for herpesvirus entry mediator) at surface level, naturally or following stable transfection, but not in cells in which this receptor was not detected by flow cytometry analysis, (ii) treatment with soluble gD induced a dose-dependent NF-kappaB activation in THP-1 cells naturally expressing HVEM, and a monoclonal antibody that prevents binding of gD to HVEM significantly reduced NF-kappaB activation by soluble gD in the same cells, (iii) coculture with transfectants expressing wild-type gD on their surface induced an approximately twofold increase in NF-kappaB activation in cells naturally expressing HVEM, while coculture with transfectants expressing a mutated form of gD, lacking its capability to bind HVEM, did not induce a similar effect and (iv) treatment with soluble gD induced a dose-dependent NF-kappaB activation in CHO transfectants expressing HVEM, but not in control CHO transfectants lacking any functional gD receptor. Overall, these results establish that HVEM is involved in NF-kappaB activation by HSV-1 gD.

Objective: Defects in Fas-mediated apoptosis are supposed to contribute to the accumulation of T lymphocytes in the gut of patients with Crohn’s disease (CD). This phenomenon has been functionally linked with the elevated expression of Flip, an inhibitor of Fas-mediated apoptosis. In this study, the molecular mechanisms that control Flip in CD were examined. Methods: Paired colonic biopsies of patients with CD, patients with ulcerative colitis (UC) and normal controls were analysed for Flip by real-time PCR and western blotting. Flip was also evaluated in CD3 + lamina propria lymphocytes (T-LPLs) cultured with tosyl phenylalanyl chloromethyl ketone (TPCK; a nuclear factor-κB (NF-κB) inhibitor), AG490 (a Janus kinase 2 (Jak2)/signal transducer and activator of transcription (Stat) inhibitor) or 17-desmethoxy-17- N , N -dimethylamino-geldanamycin (DMAG; an inhibitor of heat shock protein 90). The rate of apoptosis was examined by flow cytometry. Results: In CD, upregulation of Flip occurred at both the RNA and protein level. Treatment of CD CD3 + T-LPLs with TPCK or AG490 markedly reduced Flip RNA, suggesting a role for NF-κB and Jak/Stat pathways in the transcriptional control of Flip in this condition. Consistently, both TPCK and AG490 sensitised CD T-LPLs to Fas-mediated apoptosis. Flip protein in cells from normal gut was rapidly degraded by the proteasome pathway. In contrast, in inflamed gut of both CD and UC patients, there was a reduced degradation of Flip via the ubiquitin–proteasome-dependent pathway, but Flip expression can be decreased by DMAG. Conclusions: The data demonstrate that Flip is regulated at both the transcriptional and post-translational level in CD, and indicate that in the normal but not inflamed gut Flip is degraded via the ubiquitin–proteasome-dependent pathway.

Radiation-induced intestinal injuries, including inflammation and immune response, remain a limiting factor in the effectiveness of pelvic radiotherapy and in the patient's quality of life during and after treatment. Peroxisome proliferation-activated receptor (PPAR) agonists are now emerging as therapeutic drugs for various inflammatory diseases that are characterized by impaired PPAR expression. The purpose of this study was to investigate the profile of PPAR expression in rat colonic mucosa 3 and 7 days after abdominal γ-irradiation (10 Gy). We tested whether irradiation-induced acute inflammatory response could be modulated pharmacologically with the antiinflammatory properties of 5-aminosalicylic acid (5-ASA) (250 mg/kg/day), which is a PPAR activator. Irradiation drastically reduced mRNA and protein levels of PPARα and -γ and of the heterodimer retinoid X receptor (RXR)α at 3 days postirradiation. 5-ASA treatment normalized both PPARγ and RXRα expression at 3 days postirradiation and PPARα at 7 days. By promoting PPAR expression and its nuclear translocation, 5-ASA interfered with the nuclear factor (NF)-κB pathway, both by reducing irradiation-induced NF-κB p65 translocation/activation and increasing the expression of nuclear factor-κB inhibitor (IκB) mRNA and protein. Therefore, 5-ASA prevents irradiation-induced inflammatory processes as well as expression of tumor necrosis factor α, monocyte chemotactic protein-1, inducible nitric-oxide synthase, and macrophage infiltration. In addition, 5-ASA restores the interferon γ/signal transducer and activator of transcription (STAT)-1 and STAT-3 concentrations that were impaired at 3 and 7 days postirradiation and are correlated with suppressor of cytokine signaling-3 repression. Collectively, these results indicate that PPAR agonists may be effective in the prevention of inflammatory processes and immune responses during and after pelvic radiotherapy. Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics.

The balance between antiapoptotic and proapoptotic proteins of the Bcl-2 family is critical in determining the fate of T cells in response to death stimuli. Proapoptotic genes, such as bax, are generally regulated by the p53 family of transcription factors, whereas NF-kappaB subunits can activate the transcription of antiapoptotic Bcl-2 members. Here, we show that CD28 activation protects memory T cells from irradiation-induced apoptosis by both upregulating bcl-xL and inhibiting bax gene expression. We found that p73, but not p53, binds to and trans-activates the bax gene promoter in irradiated T cells. The activation of RelA/NF-kappaB subunit in CD28 costimulated T cells and its binding onto the bax gene promoter results in suppression of bax transcription and decrease in both p73 and RNA polymerase II recruitment in vivo. RelA recruitment on the bax gene promoter is also accompanied by the lost of p300 binding and the parallel appearance of histone deacetylase-1-containing complexes. These findings identify RelA/NF-kappaB as a critical regulator of T-cell survival by affecting the balance of Bcl-2 family members.

SUMO conjugation to proteins is involved in the regulation of diverse cellular functions. We have identified a protein, RWD-containing sumoylation enhancer (RSUME), that enhances overall SUMO-1, -2, and -3 conjugation by interacting with the SUMO conjugase Ubc9. RSUME increases noncovalent binding of SUMO-1 to Ubc9 and enhances Ubc9 thioester formation and SUMO polymerization. RSUME enhances the sumoylation of IkB in vitro and in cultured cells, leading to an inhibition of NF-kB transcriptional activity. RSUME is induced by hypoxia and enhances the sumoylation of HIF-1α, promoting its stabilization and transcriptional activity during hypoxia. Disruption of the RWD domain structure of RSUME demonstrates that this domain is critical for RSUME action. Together, these findings point to a central role of RSUME in the regulation of sumoylation and, hence, several critical regulatory pathways in mammalian cells. © 2007 Elsevier Inc. All rights reserved. Fil:Carbia-Nagashima, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Gerez, J. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Perez-Castro, C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Paez-Pereda, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Silberstein, S. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.

Propionyl-l-carnitine (PLC) has been introduced among the therapeutic approaches of peripheral arterial disease, and more recently, an increase of intimal cell apoptosis has been demonstrated to contribute to its effectiveness in rabbit carotid postinjury myointimal hyperplasia prevention. How PLC mediates these effects on vascular smooth muscle cells (SMCs) remains poorly understood. We investigated the role of NF-kappaB in PLC-induced arterial remodeling. In vivo, daily PLC treatment 15 days after injury resulted in a reduction of relative rat aortic intimal volume, an increase of apoptosis, Bax up-regulation without changing the Bcl-2 level, and a reduction of NF-kappaB, vascular cell adhesion molecule-1, monocyte chemotactic protein-1, and survivin in myointimal thickening compared with controls. In the presence of 10% serum, a reduced G(1) --S phase progression preceded PLC-induced intimal cell apoptosis; in 0.1% serum cultures, in a dose-dependent manner, PLC rapidly induced intimal cell apoptosis and reduced p65, p50, IAP-1, and IAP-2 expression. Inhibiting NF-kappaB activation through SN50 increased apoptotic rate and Bax expression in intimal but not in medial SMCs, and successive PLC treatment failed to induce a further increase in apoptotic rate. Bax antisense oligodeoxynucleotide reduced PLC-induced intimal cell apoptosis and cytochrome c release. The PLC-induced attenuation of NF-kappaB activity in intimal cells was also due to the increase of IkappaB-alpha bioavailability, as the result of a parallel induction of IkappaB-alpha synthesis and reduction of phosphorylation and degradation. Collectively, these findings document that NF-kappaB activity inhibition contributes to PLC-induced proliferative arrest and Bax-related apoptosis of intimal SMCs.