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https://www.readbyqxmd.com/read/28100773/targeted-fc%C3%AE-r-mediated-clearance-by-a-biparatopic-bispecific-antibody
#1
Srinath Kasturirangan, G Jonah Rainey, Linda Xu, Xinwei Wang, Alyse Portnoff, Tracy Chen, Christine Fazenbaker, Helen Zhong, Jared Bee, Zhutian Zeng, Craig Jenne, Herren Wu, Changshou Gao
Soluble ligands have commonly been targeted by antibody therapeutics for cancers and other diseases. While monoclonal antibodies targeting such ligands can block their interactions with their cognate receptors, they can also significantly increase the half-life of their ligands by FcRn-mediated antibody recycling, thereby evading ligand renal clearance and requiring increasingly high antibody doses to neutralize the increasing pool of target. To overcome this issue, we generated a bispecific/biparatopic antibody (BiSAb) that targets two different epitopes on IL-6 to block IL-6 mediated signaling...
January 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28095306/the-role-of-pten-in-regulation-of-hepatic-macrophages-activation-and-function-in-progression-and-reversal-of-liver-fibrosis
#2
Yahui Cheng, Yuanyao Tian, Jialu Xia, Xiaoqin Wu, Yang Yang, Xiaofeng Li, Cheng Huang, Xiaoming Meng, Taotao Ma, Jun Li
Activation of Kupffer cells (KCs) plays a pivotal role in the pathogenesis of liver fibrosis. The progression and reversal of CCl4-induced mouse liver fibrosis showed a mixed induction of hepatic classical (M1) and alternative (M2) macrophage markers. Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in modulating myeloid cell activation has recently been identified, its function in macrophage activation during hepatic fibrosis remains to be fully appreciated. In our study, PTEN expression of KCs was remarkably decreased in CCl4-induced mice but increased to a near-normal level in reversed mice...
January 14, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28091680/protective-effects-of-dietary-glycine-and-glutamic-acid-toward-the-toxic-effects-of-oxidized-mustard-oil-in-rabbits
#3
Alam Zeb, Saleem Ur Rahman
The protective role of glycine and glutamic acid against the toxic effects of oxidized oil was studied for the first time. Mustard seed oil was thermally oxidized and characterized for quality characteristics and polyphenolic composition using reversed phase HPLC-DAD. Significant changes in the quality characteristics occurred with thermal oxidation. Fourteen polyphenolic compounds were identified and quantified in oils. Quercetin-3-glucoside, quercetin-3-feruloylsophoroside, catechin, quercetin-3-rutinoside, quercetin-3,7-diglucoside, sinapic acid and vanillic acid hexoside were the major compounds in the fresh and oxidized oil...
January 16, 2017: Food & Function
https://www.readbyqxmd.com/read/28090670/an-endoplasmic-reticulum-protein-nogo-b-facilitates-alcoholic-liver-disease-through-regulation-of-kupffer-cell-polarization
#4
Jin-Kyu Park, Mingjie Shao, Moon Young Kim, Soon Koo Baik, Mee Yon Cho, Teruo Utsumi, Ayano Satoh, Xinsho Ouyang, Chuhan Chung, Yasuko Iwakiri
Background Nogo-B (Reticulon 4B) is an endoplasmic reticulum (ER) resident protein that regulates ER structure and function. Since ER stress is known to induce M2 macrophage polarization, we examined whether Nogo-B regulates M1/M2 polarization of Kupffer cells and alters the pathogenesis of alcoholic liver disease (ALD). Methods M1 and M2 phenotypes were assessed in relation to Nogo-B expression and disease severity in liver specimens from ALD patients (NCT01875211). Liver specimens from wild-type (WT) and Nogo-B knockout (KO) mice fed control or Lieber-DeCarli ethanol liquid diet (5% ethanol) for 6 weeks were analyzed for liver injury and steatosis...
January 16, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28090319/the-role-of-liver-sinusoidal-cells-in-local-hepatic-immune-surveillance
#5
REVIEW
Dirk Wohlleber, Percy A Knolle
Although the liver's function as unique immune organ regulating immunity has received a lot of attention over the last years, the mechanisms determining hepatic immune surveillance against infected hepatocytes remain less well defined. Liver sinusoidal cells, in particular, liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs), serve as physical platform for recruitment and anchoring of blood-borne immune cells in the liver. Liver sinusoidal cells also function as portal of entry for infectious microorganisms targeting the liver such as hepatotropic viruses, bacteria or parasites...
December 2016: Clinical & Translational Immunology
https://www.readbyqxmd.com/read/28088582/ripk1-protects-hepatocytes-from-kupffer-cells-mediated-tnf-induced-apoptosis-in-mouse-models-of-pamp-induced-hepatitis
#6
Aveline Filliol, Claire Piquet-Pellorce, Céline Raguénès-Nicol, Sarah Dion, Muhammad Farooq, Catherine Lucas-Clerc, Peter Vandenabeele, Mathieu J M Bertrand, Jacques Le Seyec, Michel Samson
BACKGROUND & AIMS: The severity of liver diseases is exacerbated by the death of hepatocytes, which can be induced by the sensing of Pathogen Associated Molecular Patterns (PAMPs) derived from the gut microbiota. The molecular mechanisms regulating these cell death pathways are poorly documented. In this study, we investigated the role of the Receptor Interacting Protein Kinase 1 (RIPK1), a protein known to regulate cell fate decisions, in the death of hepatocytes using two in vivo models of PAMP-induced hepatitis...
January 11, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/28077302/neutrophil-adhesion-and-crawling-dynamics-on-liver-sinusoidal-endothelial-cells-under-shear-flow
#7
Hao Yang, Ning Li, Yu Du, Chunfang Tong, Shouqin Lü, Jinrong Hu, Yan Zhang, Mian Long
Neutrophil (polymorphonuclear leukocyte, PMN) recruitment in the liver sinusoid takes place in almost all liver diseases and contributes to pathogen clearance or tissue damage. While PMN rolling unlikely appears in liver sinusoids and Mac-1 or CD44 is assumed to play respective roles during in vivo local or systematic inflammatory stimulation, the regulating mechanisms of PMN adhesion and crawling dynamics are still unclear from those in vivo studies. Here we developed a two-dimensional in vitro sinusoidal model with primary liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs) to investigate TNF-α-induced PMN recruitment under shear flow...
January 8, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28045404/liver-inflammation-and-fibrosis
#8
Yukinori Koyama, David A Brenner
Chronic liver inflammation leads to fibrosis and cirrhosis, which is the 12th leading cause of death in the United States. Hepatocyte steatosis is a component of metabolic syndrome and insulin resistance. Hepatic steatosis may be benign or progress to hepatocyte injury and the initiation of inflammation, which activates immune cells. While Kupffer cells are the resident macrophage in the liver, inflammatory cells such as infiltrating macrophages, T lymphocytes, neutrophils, and DCs all contribute to liver inflammation...
January 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28044208/hepatic-vagus-nerve-regulates-kupffer-cell-activation-via-%C3%AE-7-nicotinic-acetylcholine-receptor-in-nonalcoholic-steatohepatitis
#9
Takahiro Nishio, Kojiro Taura, Keiko Iwaisako, Yukinori Koyama, Kazutaka Tanabe, Gen Yamamoto, Yukihiro Okuda, Yoshinobu Ikeno, Kenji Yoshino, Yosuke Kasai, Masayuki Okuno, Satoru Seo, Takaki Sakurai, Masataka Asagiri, Etsuro Hatano, Shinji Uemoto
BACKGROUND: Nonalcoholic fatty liver disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH). Kupffer cells play a central role in promoting hepatic inflammation, which leads to the development of NASH. We investigated the anti-inflammatory effect of hepatic vagus-mediated stimulation of the α7 nicotinic acetylcholine receptor (α7nAChR) on Kupffer cells in NASH pathogenesis. METHODS: Wild-type (WT) mice undergoing hepatic vagotomy (HV) were fed a methionine- and choline-deficient (MCD) diet for 1 week...
January 2, 2017: Journal of Gastroenterology
https://www.readbyqxmd.com/read/28041745/contrast-enhanced-ultrasound-using-perfluorobutane-containing-microbubbles-in-the-assessment-of-liver-allograft-damage-an-exploratory-prospective-study
#10
Ijin Joo, Jae Young Lee, Dong Ho Lee, Ju Hyeon Jeon, Hyeyoung Kim, Nam-Joon Yi, Kwang-Woong Lee, Kyung-Suk Suh
This prospective study investigated the usefulness of contrast (perfluorobutane-containing microbubbles)-enhanced ultrasound in the non-invasive assessment of liver allograft damage. Forty-one liver recipients underwent contrast-enhanced ultrasound followed by a liver biopsy. The hepatic filling rate (time between the arrival of contrast agent in the right hepatic artery and the maximum intensity of hepatic parenchyma) and parenchymal intensity difference before and after instantaneous high-power emission in the Kupffer phase were measured...
December 29, 2016: Ultrasound in Medicine & Biology
https://www.readbyqxmd.com/read/28040885/gold-nanoparticle-uptake-by-human-derived-macrophages-and-primary-liver-phagocytic-cells-is-dependent-on-phenotype
#11
Sonya A MacParland, Kim M Tsoi, Ben Ouyang, Xue-Zhong Ma, Justin Manuel, Ali Fawaz, Mario A Ostrowski, Benjamin A Alman, Anton Zilman, Warren C W Chan, Ian D McGilvray
A significant challenge to delivering therapeutic doses of nanoparticles to targeted disease sites is the fact that most nanoparticles become trapped in the liver. Liver resident macrophages, or Kupffer cells, are key cells in the hepatic sequestration of nanoparticles. However, the precise role macrophage phenotype plays in nanoparticle uptake is unknown. Here, we show that human macrophage phenotype modulates hard nanoparticle uptake. Using gold nanoparticles, we examined uptake by human monocyte-derived macrophages that had been driven to a "regulatory" M2 phenotype or an "inflammatory" M1 phenotype and found that M2-type macrophages preferentially take up nanoparticles, with a clear spectrum among the subtypes (M2c>M2>M2a>M2b>M1)...
December 31, 2016: ACS Nano
https://www.readbyqxmd.com/read/28035772/deregulated-neddylation-in-liver-fibrosis
#12
Imanol Zubiete-Franco, Pablo Fernández-Tussy, Lucía Barbier-Torres, Jorge Simon, David Fernández-Ramos, Fernando Lopitz-Otsoa, Virginia Gutiérrez-de Juan, Sergio López de Davalillo, Antonio Martín Duce, Paula Iruzubieta, Daniel Taibo, Javier Crespo, Juan Caballeria, Erica Villa, Igor Aurrekoetxea, Patricia Aspichueta, Marta Varela-Rey, Shelly C Lu, José M Mato, Naiara Beraza, Teresa C Delgado, María L Martínez-Chantar
: Hepatic fibrosis is a global health problem currently without effective therapeutic approaches. Even though the ubiquitin-like posttranslational modification of neddylation, that conjugates Nedd8 (neural precursor cell expressed developmentally downregulated) to specific targets, is aberrant in many pathologies, its relevance in liver fibrosis (LF) remained unexplored. Our results show deregulated neddylation in clinical fibrosis and both in mouse bileductligation- and CCl4 -induced fibrosis...
November 7, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28035044/a-role-for-gle1-a-regulator-of-dead-box-rna-helicases-at-centrosomes-and-basal-bodies
#13
Li-En Jao, Abdalla Akef, Susan R Wente
Control of organellar assembly and function is critical to eukaryotic homeostasis and survival. Gle1 is a highly conserved regulator of RNA-dependent DEAD-box ATPase proteins, with critical roles in both mRNA export and translation. In addition to its well-defined interaction with nuclear pore complexes, here we find that Gle1 is enriched at the centrosome and basal body. Gle1 assembles into the toroid-shaped pericentriolar material around the mother centriole. Reduced Gle1 levels are correlated with decreased pericentrin localization at the centrosome and microtubule organization defects...
January 1, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28027970/hbv-inhibits-lps-induced-nlrp3-inflammasome-activation-and-il-1%C3%AE-production-via-suppressing-nf-%C3%AE%C2%BAb-pathway-and-ros-production
#14
Xin Yu, Peixiang Lan, Xuben Hou, Qiuju Han, Nan Lu, Tao Li, Chenwei Jiao, Jian Zhang, Cai Zhang, Zhigang Tian
BACKGROUND & AIMS: Hepatitis B virus (HBV) developed multifaceted strategies to evade the surveillance of immune responses, while the precise mechanisms involved remain unclear. The NLRP3 inflammasome plays crucial roles in antiviral host defense and its downstream factor IL-1β has been shown to inhibit HBV infection in vivo. The study aims to assess whether HBV can affect the NLRP3 inflammasome signaling pathways and shed light on the underlying mechanisms HBV utilizes to evade host innate immune response...
December 24, 2016: Journal of Hepatology
https://www.readbyqxmd.com/read/28018292/obesity-an-immunometabolic-perspective
#15
REVIEW
Indrani Ray, Sushil K Mahata, Rajat K De
Obesity, characterized by chronic activation of inflammatory pathways, is a critical factor contributing to insulin resistance (IR) and type 2 diabetes (T2D). Free fatty acids (FFAs) are increased in obesity and are implicated as proximate causes of IR and induction of inflammatory signaling in adipose, liver, muscle, and pancreas. Cells of the innate immune system produce cytokines, and other factors that affect insulin signaling and result in the development of IR. In the lean state, adipose tissue is populated by adipose tissue macrophage of the anti-inflammatory M2 type (ATM2) and natural killer (NK) cells; this maintains the insulin-sensitive phenotype because ATM2 cells secrete IL10...
2016: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/28012994/nanocrystal-formulations-of-a-poorly-soluble-drug-1-in-vitro-characterization-of-stability-stabilizer-adsorption-and-uptake-in-liver-cells
#16
Kalle Sigfridsson, Urban Skantze, Pia Skantze, Svante Johansson, Iain Grant, Bård Smedsrød, Britt Fuglesteg, Kjetil Elvevold, Lennart Lindfors
In the present work, milled nanocrystals of a poorly soluble compound using different stabilizers were prepared and characterized. The aim of the study was to evaluate a fundamental set of properties of the formulations prior to i.v. injection of the particles. Two polyethylene oxide containing stabilizers; (distearoyl phosphatidylethanol amine (DSPE)) -PEG2000 and the triblock copolymer Pluronic F127, were investigated, with and without polyvinylpyrrolidone K30/Aerosol OT (PVP/AOT) present. The solubility in water was around 10nM for the compound, measured from nanocrystals, but 1000 times higher in 4% human serum albumin...
December 21, 2016: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28012213/antibody-dependent-and-independent-uptake-of-hbsag-across-human-leukocyte-subsets-is-similar-between-individuals-with-chronic-hepatitis-b-virus-infection-and-healthy-donors
#17
Hugo Tharinger, Indrani Rebbapragada, Dharmaraj Samuel, Nikolai Novikov, Mindie Nguyen, Robert Jordan, Christian R Frey, Stefan Pflanz
Maintaining detectable levels of antibodies to hepatitis B surface antigen (HBsAg) in serum, i.e. HBsAg sero-conversion, is the key clinical endpoint indicative of recovery from infection with hepatitis B virus (HBV). HBV-infected hepatocytes secrete HBsAg sub-viral particles in vast excess over HBV virions. Therefore, detectable hepatitis B surface antibody (anti-HBs) titers imply complete elimination of HBV virions as well as HBsAg particles. Although intrahepatic phagocytes, e.g. Kupffer cells, are thought to mediate clearance of HBsAg via antibody (Ab)-dependent and -independent mechanisms, the relative contributions of circulating phagocytic cell types to HBsAg elimination are poorly characterized...
December 23, 2016: Journal of Viral Hepatitis
https://www.readbyqxmd.com/read/28011320/autophagy-deficient-kupffer-cells-promote-tumorigenesis-by-enhancing-mtros-nf-%C3%AE%C2%BAb-il1%C3%AE-%C3%AE-dependent-inflammation-and-fibrosis-during-the-preneoplastic-stage-of-hepatocarcinogenesis
#18
Kai Sun, Lingyun Xu, Yingying Jing, Zhipeng Han, Xiaojing Chen, Chenlei Cai, Peipei Zhao, Xue Zhao, Liqun Yang, Lixin Wei
As a cellular degradation mechanism, autophagy exerts crucial and complicated effects on HCC development. Liver non-parenchymal cells, including hepatic resident macrophage Kupffer cells, also play important roles in this process. However, most associated studies have focused on the influence of the autophagy level in hepatic cells and HCC cells, but not liver non-parenchymal cells. Based on our previous study, we confirmed that Atg5 silence in the liver during the preneoplastic stage facilitated liver fibrosis, inflammation and, ultimately, tumorigenesis...
December 20, 2016: Cancer Letters
https://www.readbyqxmd.com/read/28008658/hepatic-stellate-cells-secrete-wfa-m2bp-its-role-in-biological-interactions-with-kupffer-cells
#19
Yuki Bekki, Tomoharu Yoshizumi, Shinji Shimoda, Shinji Itoh, Norifumi Harimoto, Toru Ikegami, Atsushi Kuno, Hisashi Narimatsu, Ken Shirabe, Yoshihiko Maehara
BACKGROUND AND AIMS: Hepatic stellate cells (HSCs) play a central role in hepatic fibrosis, and are regulated by Kupffer cells (KCs). Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA(+) -M2BP) was recently identified as a serum marker for hepatic fibrosis. Although WFA(+) -M2BP was identified as a ligand of Mac-2, the function of WFA(+) -M2BP in hepatic fibrosis remains unclear. METHODS: Liver specimens were obtained from five patients with cirrhosis, five with chronic hepatitis, and five without hepatic fibrosis...
December 22, 2016: Journal of Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28007559/macrophage-mediated-clofazimine-sequestration-is-accompanied-by-a-shift-in-host-energy-metabolism
#20
Julie Trexel, Gi S Yoon, Rahul K Keswani, Cora McHugh, Larisa Yeomans, Victor Vitvitsky, Ruma Banerjee, Sudha Sud, Yihan Sun, Gus R Rosania, Kathleen A Stringer
Prolonged (8 weeks) oral administration of clofazimine results in a profound pharmacodynamic response- bioaccumulation in macrophages (including Kupffer cells) as intracellular crystal-like drug inclusions (CLDIs) with an associated increase in interleukin-1 receptor antagonist production. Notably, CLDI formation in Kupffer cells concomitantly occurs with the formation of macrophage-centric granulomas. Accordingly, we sought to understand the impact of these events on host metabolism using (1)H-nuclear magnetic resonance metabolomics...
December 19, 2016: Journal of Pharmaceutical Sciences
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