-
1.
Sesquiterpene lactones from Ambrosia arborescens Mill. inhibit pro-inflammatory cytokine expression and modulate NF-κB signaling in human skin cells.
Svensson, D, Lozano, M, Almanza, GR, Nilsson, BO, Sterner, O, Villagomez, R
Phytomedicine : international journal of phytotherapy and phytopharmacology. 2018;:118-126
Abstract
BACKGROUND Ambrosia arborescens has been used in Andean traditional medicine to reduce problems associated with various inflammatory diseases and conditions, although the underlying mechanism is unknown. HYPOTHESIS/PURPOSE The sesquiterpene lactones (SLs) coronopilin and damsin, which are major secondary metabolites of A. arborescens, have anti-inflammatory activity by attenuation of IL-6 and MCP-1 expression and inhibition of NF-κB in human dermal fibroblasts (HDFa) and human keratinocytes (HaCaT). STUDY DESIGN In order to confirm a high concentration of damsin and coronopilin in the plant material, a quantitative method was developed. The effect of the pure compounds on cytokine and NF-κB expression was examined, as well as their effects on HDFa and HaCaT cell morphology and viability. METHODS Coronopilin and damsin were quantified by HPLC-DAD analysis, from EtOAc extracts of the aerial parts of A. arborescens. Cell morphology was investigated by phase-contrast microscopy and cell viability by the MTT assay. IL-6 and MCP-1 cytokine gene expression was assessed by quantitative real-time RT-PCR in LPS stimulated cells. The NF-κB pathway was studied through western blotting of the phosphorylated forms of p65 and p50/p105, as well as the non-phosphorylated IκB. Dexamethasone was used as positive control. RESULTS Dry aerial parts contained 12.3 mg/g and 13.4 mg/g of coronopilin and damsin, respectively. Treatment with either compound (1-10 µM) for 24 h attenuated LPS-induced mRNA expression of the pro-inflammatory cytokine IL-6 and the chemokine MCP-1 in HDFa cells. The down-regulation of MCP-1 mRNA induced by coronopilin and damsin was confirmed on the protein level. Damsin reduced phosphorylated p65 and p105 subunits in HDFa cells. Neither coronopilin nor damsin affected HDFa cell morphology and viability within the used concentration range (1-10 µM). Also, in HaCaT cells, treatment with damsin (1-10 µM) for 24 h inhibited the MCP-1 expression, and damsin thereby attenuated cytokine expression both in HDFa and HaCaT cells. CONCLUSION We show that coronopilin and damsin from A. arborescens inhibit pro-inflammatory IL-6 and MCP-1 expression in human skin cells via NF-κB inhibition, suggesting that they may be useful for antagonizing inflammatory conditions of the human skin.
-
2.
Quantum Modeling: A Bridge between the Pumping and Signaling Functions of Na/K-ATPase.
Wang, W, Shapiro, JI
International journal of molecular sciences. 2018;(8)
Abstract
Although the signaling function of Na/K-ATPase has been studied for decades, the chasm between the pumping function and the signaling function of Na/K-ATPase is still an open issue. This article explores the relationship between ion pumping and signaling with attention to the amplification of oxidants through this signaling function. We specifically consider the Na/K-ATPase with respect to its signaling function as a superposition of different states described for its pumping function. We then examine how alterations in the relative amounts of these states could alter signaling through the Src-EGFR-ROS pathway. Using assumptions based on some experimental observations published by our laboratories and others, we develop some predictions regarding cellular oxidant stress.
-
3.
Cytokinin signalling regulates organ identity via the AHK4 receptor in Arabidopsis.
Pernisova, M, Grochova, M, Konecny, T, Plackova, L, Harustiakova, D, Kakimoto, T, Heisler, MG, Novak, O, Hejatko, J
Development (Cambridge, England). 2018;(14)
Abstract
Mutual interactions of the phytohormones, cytokinins and auxin determine root or shoot identity during postembryonic de novo organogenesis in plants. However, our understanding of the role of hormonal metabolism and perception during early stages of cell fate reprogramming is still elusive. Here we show that auxin activates root formation, whereas cytokinins mediate early loss of the root identity, primordia disorganisation and initiation of shoot development. Exogenous and endogenous cytokinins influence the initiation of newly formed organs, as well as the pace of organ development. The process of de novo shoot apical meristem establishment is accompanied by accumulation of endogenous cytokinins, differential regulation of genes for individual cytokinin receptors, strong activation of AHK4-mediated signalling and induction of the shoot-specific homeodomain regulator WUSCHEL. The last is associated with upregulation of isopentenyladenine-type cytokinins, revealing higher shoot-forming potential when compared with trans-zeatin. Moreover, AHK4-controlled cytokinin signalling negatively regulates the root stem cell organiser WUSCHEL RELATED HOMEOBOX 5 in the root quiescent centre. We propose an important role for endogenous cytokinin biosynthesis and AHK4-mediated cytokinin signalling in the control of de novo-induced organ identity.
-
4.
Nutrigenetic Contributions to Dyslipidemia: A Focus on Physiologically Relevant Pathways of Lipid and Lipoprotein Metabolism.
Hannon, BA, Khan, NA, Teran-Garcia, M
Nutrients. 2018;(10)
Abstract
Cardiovascular disease (CVD) remains the number one cause of death worldwide, and dyslipidemia is a major predictor of CVD mortality. Elevated lipid concentrations are the result of multiple genetic and environmental factors. Over 150 genetic loci have been associated with blood lipid levels. However, not all variants are present in pathways relevant to the pathophysiology of dyslipidemia. The study of these physiologically relevant variants can provide mechanistic understanding of dyslipidemia and identify potential novel therapeutic targets. Additionally, dietary fatty acids have been evidenced to exert both positive and negative effects on lipid profiles. The metabolism of both dietary and endogenously synthesized lipids can be affected by individual genetic variation to produce elevated lipid concentrations. This review will explore the genetic, dietary, and nutrigenetic contributions to dyslipidemia.
-
5.
Immune signalling by supramolecular assemblies.
Kumar, S, Jain, S
Immunology. 2018;(4):435-445
-
-
Free full text
-
Abstract
Formation of supramolecular assemblies appears to be a general mechanism in immune signalling pathways. These supramolecular assemblies appear to form through a nucleated polymerization mechanism. This review examines selected immune signalling pathways that involve supramolecular assemblies, describes the concepts of protein polymerization, and discusses how those concepts of protein polymerization implicate new elegant ways for signal amplification, setting threshold and noise reduction in these pathways.
-
6.
Understanding Cytoskeletal Dynamics During the Plant Immune Response.
Li, J, Staiger, CJ
Annual review of phytopathology. 2018;:513-533
Abstract
The plant cytoskeleton is a dynamic framework of cytoplasmic filaments that rearranges as the needs of the cell change during growth and development. Incessant turnover mechanisms allow these networks to be rapidly redeployed in defense of host cytoplasm against microbial invaders. Both chemical and mechanical stimuli are recognized as danger signals to the plant, and these are perceived and transduced into cytoskeletal dynamics and architecture changes through a collection of well-recognized, previously characterized players. Recent advances in quantitative cell biology approaches, along with the powerful molecular genetics techniques associated with Arabidopsis, have uncovered two actin-binding proteins as key intermediaries in the immune response to phytopathogens and defense signaling. Certain bacterial phytopathogens have adapted to the cytoskeletal-based defense mechanism during the basal immune response and have evolved effector proteins that target actin filaments and microtubules to subvert transcriptional reprogramming, secretion of defense-related proteins, and cell wall-based defenses. In this review, we describe current knowledge about host cytoskeletal dynamics operating at the crossroads of the molecular and cellular arms race between microbes and plants.
-
7.
The molecular aspects of oxidative & nitrosative stress and the tryptophan catabolites pathway (TRYCATs) as potential causes of depression.
Wigner, P, Czarny, P, Galecki, P, Su, KP, Sliwinski, T
Psychiatry research. 2018;:566-574
Abstract
Depression is the most common mental disorder in the world. It is estimated that 350 million people suffer from depression worldwide. Depressive disorders will have become the second most frequent health problem globally by the year 2020, just behind ischemic heart disease. The causes of depressive disorders are not fully known. Previous studies showed that impaired tryptophan catabolites pathway, oxidative and nitrosative stress may play an important role in the pathogenesis of depression. Patients with depression have lower plasma levels of superoxide dismutase and glutathione peroxidise in comparison to controls. Moreover, depressed patients are characterized by decreased plasma levels of zinc, coenzyme Q10, albumin, uric acid, vitamin E and glutathione. Abnormal nitric oxidative production and nitric oxide synthase activity are also associated with depression. A dysfunction of the tryptophan catabolites pathway, indicated by increased levels of tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase, is also involved in the development of depression. Furthermore, increased levels of kynurenine and quinolinic acid might cause depression. Moreover, studies to date indicate that 8-oxyguanine, malondialdehyde, and 8-iso-prostaglandin F2α may serve as possible biomarkers. Additionally, regulation of defective mechanisms may provide a promising direction for the development of new and effective therapies.
-
8.
Vitamin D downregulates the IL-23 receptor pathway in human mucosal group 3 innate lymphoid cells.
Konya, V, Czarnewski, P, Forkel, M, Rao, A, Kokkinou, E, Villablanca, EJ, Almer, S, Lindforss, U, Friberg, D, Höög, C, et al
The Journal of allergy and clinical immunology. 2018;(1):279-292
Abstract
BACKGROUND Vitamin D deficiency is a risk factor for inflammatory bowel disease (IBD). The IL-23-driven tissue-resident group 3 innate lymphoid cells (ILC3s) play essential roles in intestinal immunity, and targeting IL-23/12 is a promising approach in IBD therapy. OBJECTIVE We set out to define the role of 1α,25-dihydroxy vitamin D3 (1,25D) in regulating functional responses of human mucosal ILC3s to IL-23 plus IL-1β stimulation. METHODS Transcriptomes of sorted tonsillar ILC3s were assessed by using microarray analysis. ILC3 cytokine production, proliferation, and differentiation were determined by means of flow cytometry, ELISA, and multiplex immunoassay. Intestinal cell suspensions and ILC3s sorted from gut biopsy specimens of patients with IBD were also analyzed along with plasma 25-hydroxy vitamin D3 (25D) detection. RESULTS ILC3s stimulated with IL-23 plus IL-1β upregulated the vitamin D receptor and responded to 1,25D with downregulation of the IL-23 receptor pathway. Consequently, 1,25D suppressed IL-22, IL-17F, and GM-CSF production from tonsillar and gut ILC3s. In parallel, 1,25D upregulated genes linked to the IL-1β signaling pathway, as well as the IL-1β-inducible cytokines IL-6, IL-8, and macrophage inflammatory protein 1α/β. The 1,25D-triggered skewing in ILC3 function was not accompanied or caused by changes in viability, proliferation, or phenotype. Finally, we confirmed low 25D plasma levels in patients with IBD with active inflammation. CONCLUSION In light of the beneficial targeting of IL-23/12 in patients with IBD, 1,25D appears as an interesting therapeutic agent that inhibits the IL-23 receptor pathway, providing a novel mechanism for how ILC3s could be manipulated to regulate intestinal inflammation.
-
9.
Akt and mTORC1 signaling as predictive biomarkers for the EGFR antibody nimotuzumab in glioblastoma.
Ronellenfitsch, MW, Zeiner, PS, Mittelbronn, M, Urban, H, Pietsch, T, Reuter, D, Senft, C, Steinbach, JP, Westphal, M, Harter, PN
Acta neuropathologica communications. 2018;(1):81
Abstract
Glioblastoma (GB) is the most frequent primary brain tumor in adults with a dismal prognosis despite aggressive treatment including surgical resection, radiotherapy and chemotherapy with the alkylating agent temozolomide. Thus far, the successful implementation of the concept of targeted therapy where a drug targets a selective alteration in cancer cells was mainly limited to model diseases with identified genetic drivers. One of the most commonly altered oncogenic drivers of GB and therefore plausible therapeutic target is the epidermal growth factor receptor (EGFR). Trials targeting this signaling cascade, however, have been negative, including the phase III OSAG 101-BSA-05 trial. This highlights the need for further patient selection to identify subgroups of GB with true EGFR-dependency. In this retrospective analysis of treatment-naïve samples of the OSAG 101-BSA-05 trial cohort, we identify the EGFR signaling activity markers phosphorylated PRAS40 and phosphorylated ribosomal protein S6 as predictive markers for treatment efficacy of the EGFR-blocking antibody nimotuzumab in MGMT promoter unmethylated GBs. Considering the total trial population irrespective of MGMT status, a clear trend towards a survival benefit from nimotuzumab was already detectable when tumors had above median levels of phosphorylated ribosomal protein S6. These results could constitute a basis for further investigations of nimotuzumab or other EGFR- and downstream signaling inhibitors in selected patient cohorts using the reported criteria as candidate predictive biomarkers.
-
10.
Inflammatory bowel disease therapy: blockade of cytokines and cytokine signaling pathways.
Yamamoto-Furusho, JK
Current opinion in gastroenterology. 2018;(4):187-193
Abstract
PURPOSE OF REVIEW Treatment of inflammatory bowel disease (IBD) patients can vary depending on the degree of response, lack of response or intolerance to conventional or biological agents aimed at blocking various cytokines or integrins. Recent therapies targeting several cytokines were reviewed to evaluate efficacy in IBD patients. RECENT FINDINGS Ustekinumab is an interleukin inhibitor which blocks the p40 subunit of IL-12 and IL-23 axis and is already approved for the treatment of Crohn's disease patients, specially those who had inadequate response or intolerance to conventional treatment with anti-TNF-α agents. Several treatments have been developed that are focused on the blockade of specific cytokines such as IL-6, IL-12, IL-13, IL-17, IL-23 and a chemokine named IFN-γ-inducible protein-10 as well as some oral small-molecule inhibitors of intracellular cytoplasmic tyrosine kinases like tofacitinib, filgotinib and upadacitinib. SUMMARY Several biologics blocking different and specific cytokines and oral small molecule agents have been and are being evaluated in IBD patients. A comprehensive understanding of the underlying immunological mechanisms will allow to develop effective and safe agents that inhibit one or more cytokines to improve the outcome in patients with IBD.