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(1) Protective role of c-Jun N-terminal kinase-2 (JNK2) in ibuprofen-induced acute liver injury.[TOP]

Pubmed ID :30264435
Publication Date : //
Ibuprofen is a worldwide used non-steroidal anti-inflammatory drug (NSAID) which may cause acute liver injury (ALI) requiring liver transplantation. We aimed to unveil the molecular pathways involved in triggering ibuprofen-induced ALI, which, at present, remain elusive. First, we investigated activation of essential pathways in human liver sections of ibuprofen-induced ALI. Next, we assessed the cytotoxicity of ibuprofen in vitro and developed a novel murine model of ibuprofen intoxication. To assess the role of JNK, we used animals carrying constitutive deletion of c-Jun N-terminal kinase 1 (Jnk1 ) or Jnk2 (Jnk2 ) expression and included investigations using animals with hepatocyte-specific Jnk deletion either genetically (Jnk1 ) or by siRNA (siJnk2 ). We found in human and murine samples of ibuprofen-induced acute liver failure (ALF) that JNK phosphorylation was increased in the cytoplasm of hepatocytes and other non-liver parenchymal cells (LPCs) compared with healthy tissue. In mice, ibuprofen intoxication resulted in a significantly stronger degree of liver injury compared with vehicle-treated controls as evidenced by serum transaminases, and hepatic histopathology. Next, we investigated molecular pathways. PKCα, AKT, JNK and RIPK1 were significantly increased 8 h after ibuprofen intoxication. Constitutive Jnk1 and Jnk2 deficient mice exhibited increased liver dysfunction compared to wildtype (WT) animals. Furthermore, siJnk2 animals showed a dramatic increase in biochemical markers of liver function, which correlated with significantly higher serum liver enzymes and worsened liver histology, and MAPK activation compared to Jnk1 or WT animals. In our study, cytoplasmic JNK activation in hepatocytes and other non-LPCs is a hallmark of human and murine ibuprofen-induced ALI. Functional in vivo analysis demonstrated a protective role of hepatocyte-specific Jnk2 during ibuprofen ALI.

Authors : Zoubek Miguel Eugenio, Woitok Marius Maximilian, Sydor Svenja, Nelson Leonard J, Bechmann Lars P, Lucena Maria Isabel, Andrade Raul J, Bast Aalt, Koek Ger H, Trautwein Christian, Cubero Francisco Javier,

(2) Novel amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids as multifunctional TRPA1 antagonists and PDE4/7 inhibitors: A new approach for the treatment of pain.[TOP]

Pubmed ID :30245393
Publication Date : //
A series of novel amide derivatives of 1,3-dimethyl-2,6-dioxopurin-7-yl-alkylcarboxylic acids designed using a structure-based computational approach was synthesized and assayed to evaluate their ability to block human TRPA1 channel and inhibit PDE4B/7A activity. We identified compounds 16 and 27 which showed higher potency against TRPA1 compared to HC-030031. In turn, compound 36 was the most promising multifunctional TRPA1 antagonist and PDE4B/7A dual inhibitor with IC values in the range of that of the reference rolipram and BRL-50481, respectively. Compound 36 as a combined TRPA1/PDE4B/PDE7A ligand was characterized by a distinct binding mode in comparison to 16 and 27, in the given protein targets. The inhibition of both cAMP-specific PDE isoenzymes resulted in a strong anti-TNF-α effect of 36in vivo. Moreover, the potent anti-inflammatory and analgesic efficacy of 36 was observed in animal models of pain and inflammation (formalin test in mice and carrageenan-induced paw edema in rats). This compound also displayed significant antiallodynic properties in the early phase of chemotherapy-induced peripheral neuropathy in mice. In turn, the pure TRPA1 antagonists 16 and 27 revealed a statistically significant antiallodynic effect in the formalin test and in the von Frey test performed in both phases of oxaliplatin-induced allodynia. Antiallodynic activity of the test compounds 16, 27 and 36 was observed at a dose range comparable to that of the reference drug - pregabalin. In conclusion, the proposed approach of pain treatment based on the concomitant blocking of TRPA1 channel and PDE4B/7A inhibitory activity appears to be interesting research direction for the future search for novel analgesics.

Authors : Chłoń-Rzepa Grażyna, Ślusarczyk Marietta, Jankowska Agnieszka, Gawalska Alicja, Bucki Adam, Kołaczkowski Marcin, Świerczek Artur, Pociecha Krzysztof, Wyska Elżbieta, Zygmunt Małgorzata, Kazek Grzegorz, Sałat Kinga, Pawłowski Maciej,

(3) Novel antibodies against GPIbα inhibit pulmonary metastasis by affecting vWF-GPIbα interaction.[TOP]

Pubmed ID :30223883
Publication Date : //
Platelet glycoprotein Ibα (GPIbα) extracellular domain, which is part of the receptor complex GPIb-IX-V, plays an important role in tumor metastasis. However, the mechanism through which GPIbα participates in the metastatic process remains unclear. In addition, potential bleeding complication remains an obstacle for the clinical use of anti-platelet agents in cancer therapy.

Authors : Qi Yingxue, Chen Wenchun, Liang Xinyu, Xu Ke, Gu Xiangyu, Wu Fengying, Fan Xuemei, Ren Shengxiang, Liu Junling, Zhang Jun, Li Renhao, Liu Jianwen, Liang Xin,

(4) Selective Inhibition of ADAM28 Suppresses Lung Carcinoma Cell Growth and Metastasis.[TOP]

Pubmed ID :30190423
Publication Date : //
ADAM28 (a disintegrin and metalloproteinase 28) is overexpressed by carcinoma cells in non-small cell lung carcinomas (NSCLC) and plays an important role in cancer cell proliferation and metastasis by reactivation of insulin-like growth factor-1 (IGF-1) and escaping from von Willebrand factor (VWF)-induced apoptosis through digestion of IGF-binding protein-3 and VWF, respectively. To aim for new target therapy of NSCLC patients, we developed human neutralizing antibodies 211-12 and 211-14 against ADAM28, which showed IC values of 62.4 and 37.5 nmol/L, respectively. Antibody 211-14 recognized the junctional region between cysteine-rich domain and secreted-specific domain and showed a K value of 94.7 pmol/L for the epitope-containing peptide. This antibody detected monkey and human secreted-form ADAM28s, although it was not reactive with mouse membrane-anchored ADAM28m. Antibody 211-14 effectively inhibited IGF-1-stimulated cell proliferation of lung adenocarcinoma cell lines with ADAM28 expression, including PC-9 cells, and promoted VWF-induced cell death in these cell lines. In lung metastasis models, antibody 211-14 significantly reduced tumor growth and metastases of PC-9 cells and prolonged survivals in the antibody-treated mice compared with the control IgG-treated ones. Combination therapy of the antibody and docetaxel was more effective than that of bevacizumab and docetaxel and showed further elongation of survival time compared with monotherapy. No adverse effects were observed even after administration of 10-fold more than effective dose of anti-ADAM28 antibody to normal mice. Our data demonstrate that antibody 211-14 is a neutralizing antibody specific to ADAM28s and suggest that this antibody may be a useful treatment remedy for NSCLC patients.

Authors : Mochizuki Satsuki, Shimoda Masayuki, Abe Hitoshi, Miyamae Yuka, Kuramoto Junko, Aramaki-Hattori Noriko, Ishii Ken, Ueno Hideki, Miyakoshi Akira, Kojoh Kanehisa, Okada Yasunori,

(5) Influence of Phosphatidylinositol-3-Kinase/Protein Kinase B-Mammalian Target of Rapamycin Signaling Pathway on the Neuropathic Pain Complicated by Nucleoside Reverse Transcriptase Inhibitors for the Treatment of HIV Infection.[TOP]

Pubmed ID :30058583
Publication Date : //
Nucleoside reverse transcriptase inhibitors (NRTIs) are the earliest and most commonly used anti-human immunodeficiency virus drugs and play an important role in high active antiretroviral therapy. However, NRTI drug therapy can cause peripheral neuropathic pain. In this study, we aimed to investigate the mechanisms of rapamycin on the pain sensitization of model mice by in vivo experiments to explore the effect of mammalian target of rapamycin (mTOR) in the pathogenesis of neuropathic pain caused by NRTIs.

Authors : Cheng Hao, Wu Liang-Yu,

(6) Discovery of a benzenesulfonamide-based dual inhibitor of microsomal prostaglandin E synthase-1 and 5-lipoxygenase that favorably modulates lipid mediator biosynthesis in inflammation.[TOP]

Pubmed ID :30053720
Publication Date : //
Leukotrienes (LTs) and prostaglandin (PG)E, produced by 5-lipoxygenase (5-LO) and microsomal prostaglandin E synthase-1 (mPGES-1), respectively, are key players in inflammation, and pharmacological suppression of these lipid mediators (LM) represents a strategy to intervene with inflammatory disorders. Previous studies revealed that the benzenesulfonamide scaffold displays efficient 5-LO-inhibitory properties. Here, we structurally optimized benzenesulfonamides which led to an N-phenylbenzenesulfonamide derivative (compound 47) with potent inhibitory activities (IC = 2.3 and 0.4 μM for isolated 5-LO and 5-LO in intact cells, respectively). Compound 47 prevented the interaction of 5-LO with its activating protein (FLAP) at the nuclear envelope in transfected HEK293 cells as shown by in situ proximity ligation assay. Comprehensive assessment of the LM profile produced by human macrophages revealed the ability of 47 to selectively down-regulate pro-inflammatory LMs (i.e. LTs and PGE) in M1 but to enhance the formation of pro-resolving LMs (i.e. resolvins and maresins) in M2 macrophages. Moreover, 47 strongly inhibited LT formation and cell infiltration in two in vivo models of acute inflammation (i.e., peritonitis and air pouch sterile inflammation in mice). Together, 47 represents a novel LT biosynthesis inhibitor with an attractive pharmacological profile as anti-inflammatory drug that also promotes the biosynthesis of pro-resolving LM.

Authors : Cheung Sun-Yee, Werner Markus, Esposito Lucia, Troisi Fabiana, Cantone Vincenza, Liening Stefanie, König Stefanie, Gerstmeier Jana, Koeberle Andreas, Bilancia Rossella, Rizza Roberta, Rossi Antonietta, Roviezzo Fiorentina, Temml Veronika, Schuster Daniela, Stuppner Hermann, Schubert-Zsilavecz Manfred, Werz Oliver, Hanke Thomas, Pace Simona,

(7) The role of Sprouty1 in the proliferation, differentiation and apoptosis of epidermal keratinocytes.[TOP]

Pubmed ID :30039569
Publication Date : //
Sprouty (SPRY) 1 is one of the SPRY proteins that inhibits signalling from various growth factors pathways and has also been known as a tumour suppressor in various malignancies. However, no study elucidates the role of SPRY1 in the skin. Our study was conducted to determine the function of SPRY1 in human keratinocytes and the epidermis.

Authors : Wang Ping, Zhou Yuan, Yang Jian-Qiang, Landeck Lilla, Min Min, Chen Xi-Bei, Chen Jia-Qi, Li Wei, Cai Sui-Qing, Zheng Min, Man Xiao-Yong,

(8) No Significant Role for Smooth Muscle Cell Mineralocorticoid Receptors in Atherosclerosis in the Apolipoprotein-E Knockout Mouse Model.[TOP]

Pubmed ID :30038907
Publication Date : //
Elevated levels of the hormone aldosterone are associated with increased risk of myocardial infarction and stroke in humans and increased progression and inflammation of atherosclerotic plaques in animal models. Aldosterone acts through the mineralocorticoid receptor (MR) which is expressed in vascular smooth muscle cells (SMCs) where it promotes SMC calcification and chemokine secretion . The objective of this study is to explore the role of the MR specifically in SMCs in the progression of atherosclerosis and the associated vascular inflammation in the apolipoprotein E knockout (ApoE) mouse model. Male ApoE mice were bred with mice in which MR could be deleted specifically from SMCs by tamoxifen injection. The resulting atheroprone SMC-MR-KO mice were compared to their MR-Intact littermates after high fat diet (HFD) feeding for 8 or 16 weeks or normal diet for 12 months. Body weight, tail cuff blood pressure, heart and spleen weight, and serum levels of glucose, cholesterol, and aldosterone were measured for all mice at the end of the treatment period. Serial histologic sections of the aortic root were stained with Oil Red O to assess plaque size, lipid content, and necrotic core area; with PicroSirius Red for quantification of collagen content; by immunofluorescent staining with anti-Mac2/Galectin-3 and anti-smooth muscle α-actin antibodies to assess inflammation and SMC marker expression; and with Von Kossa stain to detect plaque calcification. In the 16-week HFD study, these analyses were also performed in sections from the brachiocephalic artery. Flow cytometry of cell suspensions derived from the aortic arch was also performed to quantify vascular inflammation after 8 and 16 weeks of HFD. Deletion of the MR specifically from SMCs did not significantly change plaque size, lipid content, necrotic core, collagen content, inflammatory staining, actin staining, or calcification, nor were there differences in the extent of vascular inflammation between MR-Intact and SMC-MR-KO mice in the three experiments. SMC-MR does not directly contribute to the formation, progression, or inflammation of atherosclerotic plaques in the ApoE mouse model of atherosclerosis. This indicates that the MR in non-SMCs mediates the pro-atherogenic effects of MR activation.

Authors : Moss M Elizabeth, DuPont Jennifer J, Iyer Surabhi L, McGraw Adam P, Jaffe Iris Z,

(9) Anti-inflammatory Effects of the Octapeptide NAP in Human Microbiota-Associated Mice Suffering from Subacute Ileitis.[TOP]

Pubmed ID :29997909
Publication Date : //
The octapeptide NAP is well known for its neuroprotective properties. We here investigated whether NAP treatment could alleviate pro-inflammatory immune responses during experimental subacute ileitis. To address this, mice with a human gut microbiota were perorally infected with one cyst of (day 0) and subjected to intraperitoneal synthetic NAP treatment from day 1 until day 8 postinfection (p.i.). Whereas placebo (PLC) control animals displayed subacute ileitis at day 9 p.i., NAP-treated mice exhibited less pronounced pro-inflammatory immune responses as indicated by lower numbers of intestinal mucosal T and B lymphocytes and lower interferon (IFN)- concentrations in mesenteric lymph nodes. The NAP-induced anti-inflammatory effects were not restricted to the intestinal tract but could also be observed in extra-intestinal including systemic compartments, given that pro-inflammatory cytokines were lower in liver, kidney, and lung following NAP as compared to PLC application, whereas at day 9 p.i., colonic and serum interleukin (IL)-10 concentrations were higher in the former as compared to the latter. Remarkably, probiotic commensal bifidobacterial loads were higher in the ileal lumen of NAP as compared to PLC-treated mice with ileitis. Our findings thus further support that NAP might be regarded as future treatment option directed against intestinal inflammation.

Authors : Escher Ulrike, Giladi Eliezer, Dunay Ildikò R, Bereswill Stefan, Gozes Illana, Heimesaat Markus M,

(10) CEACAM1 promotes CD8 T cell responses and improves control of a chronic viral infection.[TOP]

Pubmed ID :29967450
Publication Date : //
Dysfunction of CD8 T cells can lead to the development of chronic viral infection. Identifying mechanisms responsible for such T cell dysfunction is therefore of great importance to understand how to prevent persistent viral infection. Here we show using lymphocytic choriomeningitis virus (LCMV) infection that carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is fundamental for recruiting lymphocyte-specific protein kinase (Lck) into the T cell receptor complex to form an efficient immunological synapse. CEACAM1 is essential for activation of CD8 T cells, and the absence of CEACAM1 on virus-specific CD8 T cells limits the antiviral CD8 T cell response. Treatment with anti-CEACAM1 antibody stabilizes Lck in the immunological synapse, prevents CD8 T cell exhaustion, and improves control of virus infection in vivo. Treatment of human virus-specific CD8 T cells with anti-CEACAM1 antibody similarly enhances their proliferation. We conclude that CEACAM1 is an important regulator of virus-specific CD8 T cell functions in mice and humans and represents a promising therapeutic target for modulating CD8 T cells.

Authors : Khairnar Vishal, Duhan Vikas, Patil Ashwini M, Zhou Fan, Bhat Hilal, Thoens Christine, Sharma Piyush, Adomati Tom, Friendrich Sarah-Kim, Bezgovsek Judith, Dreesen Janine D, Wennemuth Gunther, Westendorf Astrid M, Zelinskyy Gennadiy, Dittmer Ulf, Hardt Cornelia, Timm Jörg, Göthert Joachim R, Lang Philipp A, Singer Bernhard B, Lang Karl S,