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American Journal of Pathology

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https://www.readbyqxmd.com/read/28935578/abin1-determines-severity-of-glomerulonephritis-via-activation-of-intrinsic-glomerular-inflammation
#1
Erik A Korte, Dawn J Caster, Michelle T Barati, Min Tan, Shirong Zheng, Celine C Berthier, Frank C Brosius, Mark B Vieyra, Ryan M Sheehan, Michele Kosiewicz, Marcin Wysoczynski, Patrick M Gaffney, David J Salant, Kenneth R McLeish, David W Powell
Transcription factor NF-κB regulates expression of numerous genes that control inflammation and is activated in glomerular cells in glomerulonephritis (GN). We previously identified genetic variants for a NF-κB regulatory, ubiquitin binding protein ABIN1 as risk factors for GN in systemic autoimmunity. The goal here was to define glomerular inflammatory events controlled by ABIN1 function in GN. Nephrotoxic serum nephritis was induced in wild-type (WT) and ubiquitin binding deficient ABIN1[D485N] mice; and renal pathophysiology and glomerular inflammatory phenotypes were assessed...
September 18, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28935577/human-pancreatic-acinar-cells-proteomic-characterization-physiologic-responses-and-organellar-disorders-in-ex-vivo-pancreatitis
#2
Aurelia Lugea, Richard T Waldron, Olga A Mareninova, Natalia Shalbueva, Nan Deng, Hsin-Yuan Su, Diane D Thomas, Elaina K Jones, Scott W Messenger, Jiayue Yang, Cheng Hu, Ilya Gukovsky, Zhenqiu Liu, Guy E Groblewski, Anna S Gukovskaya, Fred S Gorelick, Stephen J Pandol
Knowledge of the molecular mechanisms of acute pancreatitis is largely based on studies using rodents. To assess similar mechanisms in humans, we performed ex vivo pancreatitis studies in human acini isolated from cadaveric pancreata from organ donors. Since data on these human acinar preparations are sparse, we assessed their functional integrity, and cellular and organellar morphology using light, fluorescence and electron microscopy; and their proteome by liquid chromatography-tandem mass spectrometry (LC-MS/MS)...
September 18, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28935576/myofilament-remodeling-and-function-is-more-impaired-in-peripartum-cardiomyopathy-compared-to-dilated-cardiomyopathy-and-ischemic-heart-disease
#3
Ilse Anne Elise Bollen, Elisabeth Ehler, Karin Fleischanderl, Floor Bouwman, Lanette Kempers, Melanie Ricke-Hoch, Denise Hilfiker-Kleiner, Cristobal Guillermo Dos Remedios, Martina Krüger, Aryan Vink, Folkert Wouter Asselbergs, Karin Yvon van Spaendonck-Zwarts, Yigal Martin Pinto, Diederik Wouter Dimitri Kuster, Jolanda van der Velden
Peripartum cardiomyopathy (PPCM) and dilated cardiomyopathy (DCM) show similarities in clinical presentation. However, while DCM patients do not recover and slowly deteriorate further, PPCM patients show either a fast cardiac deterioration or complete recovery. The aim of this study was to assess if underlying cellular changes can explain the clinical similarities and differences in the two diseases. We therefore assessed sarcomeric protein expression, modification, titin isoform shift, and contractile behavior of cardiomyocytes in heart tissue of PPCM and DCM patients and compared these to non-failing controls...
September 18, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28935575/non-pathological-infection-of-macaques-by-an-attenuated-mycobacterial-vaccine-is-not-reactivated-in-the-setting-of-hiv-coinfection
#4
Taylor Wayne Foreman, Ashley Victoria Veatch, Denae Nadine LoBato, Peter John Didier, Lara Angela Doyle-Meyers, Kasi Elizabeth Russell-Lodrigue, Andrew Alan Lackner, Konstantin Gus Kousoulas, Shabaana Abdul Khader, Deepak Kaushal, Smriti Mehra
Failure to replace BCG with efficacious anti-TB vaccines have prompted out-of-the-box thinking, including pulmonary vaccination in order to elicit local immunity. MtbΔsigH, a stress-response attenuated strain, protected against lethal TB when used to vaccinate macaques via inhalation. While live mycobacterial vaccines show promising efficacy, HIV co-infection and the resulting immunodeficiency prompts safety concerns about their use. We assessed the persistence and safety of MtbΔsigH, delivered directly to the lungs, in the setting of HIV coinfection...
September 18, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28935574/taurocholate-induces-biliary-differentiation-of-liver-progenitor-cells-causing-hepatic-stellate-cell-chemotaxis-in-the-ductular-reaction-role-in-pediatric-cystic-fibrosis-liver-disease
#5
Katarzyna N Pozniak, Michael A Pearen, Tamara N Pereira, Cynthia Sm Kramer, Priyakshi Kalita-De Croft, Sujeevi K Nawaratna, Manuel A Fernandez-Rojo, Geoffrey N Gobert, Janina Ee Tirnitz-Parker, John K Olynyk, Ross W Shepherd, Peter J Lewindon, Grant A Ramm
Cystic fibrosis liver disease (CFLD) in children causes progressive fibrosis leading to biliary cirrhosis, however its cause(s) and early pathogenesis are unclear. We hypothesised that a bile acid-induced Ductular Reaction (DR) drives fibrogenesis. We evaluated the DR by cytokeratin-7 immunohistochemistry in liver biopsies, staged for fibrosis, from 60 children with CFLD and demonstrated that the DR was significantly correlated with hepatic fibrosis stage and biliary taurocholate levels. To examine the mechanisms involved in DR induction liver progenitor cells (LPCs) were treated with taurocholate and key events in DR evolution were assessed: LPC proliferation, LPC biliary differentiation and hepatic stellate cell (HSC) chemotaxis...
September 18, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28935573/acrolein-disrupts-tight-junction-proteins-and-causes-er-stress-mediated-epithelial-cell-death-leading-to-intestinal-barrier-dysfunction-and-permeability
#6
Wei-Yang Chen, Min Wang, Jingwen Zhang, Shirish S Barve, Craig J McClain, Swati Joshi-Barve
Increasing evidence suggests that environmental and dietary factors can affect intestinal epithelial integrity leading to gut permeability and bacterial translocation. Intestinal barrier dysfunction is a pathogenic process associated with many chronic disorders. Acrolein is an environmental and dietary pollutant and a lipid-derived endogenous metabolite. The impact of acrolein on the intestine has not been investigated before and is evaluated in this study, both in vitro and in vivo. Our data demonstrate that oral acrolein exposure in mice caused damage to the intestinal epithelial barrier, resulting in increased permeability and subsequently translocation of bacterial endotoxin-LPS into the blood...
September 18, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28935572/macrophage-infiltration-is-a-causative-factor-for-ligamentum-flavum-hypertrophy-through-the-activation-of-collagen-production-in-fibroblasts
#7
Takeyuki Saito, Masamitsu Hara, Hiromi Kumamaru, Kazu Kobayakawa, Kazuya Yokota, Ken Kijima, Shingo Yoshizaki, Katsumi Harimaya, Yoshihiro Matsumoto, Kenichi Kawaguchi, Mitsumasa Hayashida, Yutaka Inagaki, Keiichiro Shiba, Yasuharu Nakashima, Seiji Okada
Ligamentum flavum (LF) hypertrophy causes lumbar spinal canal stenosis, leading to leg pain and disability in activities of daily living in elderly individuals. Although there have been previous studies on LF hypertrophy, its pathomechanisms have not been fully elucidated. In this study, we demonstrated that infiltrating macrophages were a causative factor for LF hypertrophy. Induction of macrophages into the mouse LF by applying a micro-injury resulted in LF hypertrophy along with collagen accumulation and fibroblasts proliferation at the injured site, which were very similar to the characteristics observed in the severely hypertrophied LF of human...
September 18, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28935571/aggravated-post-infarct-heart-failure-in-type-2-diabetes-is-associated-with-impaired-mitophagy-and-exaggerated-inflammasome-activation
#8
Thota Durga Devi, Mohan Babu, Petri Mäkinen, Minna Kaikkonen, Merja Heinaniemi, Hanne Laakso, Elias Ylä-Herttuala, Lassi Rieppo, Timo Liimatainen, Nikolay Naumenko, Pasi Tavi, Seppo Ylä-Herttuala
Type 2 diabetes mellitus (T2DM) is a major risk factor for heart disease. Mortality rates following myocardial infarction (MI) are significantly increased in T2DM patients due to dysfunctional left ventricle (LV). However, molecular pathways underlying accelerated post-MI heart failure (HF) in T2DM remain unclear. We investigated the underlying mechanisms by inducing MI in a well-established model of T2DM and control mice. Cardiac imaging revealed a significantly decreased global LV ejection fraction (EF) in parallel with increased mortality post-MI in T2DM mice compared to controls...
September 18, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28935570/molecular-alterations-in-a-mouse-cardiac-model-of-friedreich-s-ataxia-an-impaired-nrf2-response-mediated-via-up-regulation-of-keap1-and-activation-of-the-gsk3%C3%AE-axis
#9
Amy Anzovino, Shannon Chiang, Bronwyn E Brown, Clare L Hawkins, Des R Richardson, Michael L-H Huang
Nuclear factor-erythroid 2-related factor-2 (Nrf2) is a master regulator of the anti-oxidant response. However, studies in models of Friedreich's ataxia (FA), a neuro- and cardio-degenerative disease associated with oxidative stress, reported decreased Nrf2 expression due to unknown mechanisms. Using a mouse conditional frataxin knockout (KO) model in the heart and skeletal muscle, we examined the Nrf2 pathway in these tissues. Frataxin KO results in fatal cardiomyopathy, while skeletal muscle was asymptomatic...
September 18, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28935569/constitutive-cd40-signaling-in-dendritic-cells-limits-atherosclerosis-by-provoking-inflammatory-bowel-disease-and-ensuing-cholesterol-malabsorption
#10
Pascal Kusters, Tom Seijkens, Christina Bürger, Bart Legein, Holger Winkels, Marion Gijbels, Christian Barthels, Remy Bennett, Linda Beckers, Dorothee Atzler, Erik Biessen, Thomas Brocker, Christian Weber, Norbert Gerdes, Esther Lutgens
The co-stimulatory molecule CD40 is a major driver of atherosclerosis. It is expressed on a wide variety of cell types including mature dendritic cells (DCs) and is required for optimal T cell activation and expansion. It remains undetermined if and how CD40 on DCs impacts the pathogenesis of atherosclerosis. Here we examined the effects of constitutively active CD40 in DCs on atherosclerosis, using low-density lipoprotein-deficient (Ldlr(-/-)) bone-marrow chimeras that express a transgene containing an engineered latent membrane protein 1 (LMP)/CD40 fusion protein conferring constitutive CD40 signaling under control of the DC-specific CD11c promoter (DC-LMP1/CD40)...
September 18, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28923684/ikk%C3%AE-activation-in-the-fetal-lung-mesenchyme-alters-lung-vascular-development-but-not-airway-morphogenesis
#11
Alyssa M McCoy, Jennifer L Herington, Ashley N Stouch, Anamika B Mukherjee, Omar Lakhdari, Timothy S Blackwell, Lawrence S Prince
In the immature lung, inflammation and injury disrupt epithelial-mesenchymal interactions required for normal development. Innate immune signaling and NF-κB activation disrupt the normal expression of multiple mesenchymal genes playing key roles in airway branching and alveolar formation. To test the role of the NF-κB pathway specifically in lung mesenchyme, we utilized the mesenchymal Twist2-Cre to drive expression of a constitutively active IKKβ mutant (IKKβca) in developing mice. Embryonic Twist2-IKKβca mice were generated in expected numbers and appeared grossly normal...
September 15, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28919113/hepatic-tmem30a-deficiency-causes-intrahepatic-cholestasis-by-impairing-expression-and-localization-of-bile-salt-transporters
#12
Leiming Liu, Lingling Zhang, Lin Zhang, Fan Yang, Xudong Zhu, Zhongjie Lu, Yeming Yang, Haiqi Lu, Lifeng Feng, Zhuo Wang, Hui Chen, Sheng Yan, Lin Wang, Zhenyu Ju, Hongchuan Jin, Xianjun Zhu
Mutations in ATP8B1 or ATP11C (members of P4-type ATPases) cause progressive familial intrahepatic cholestasis type 1 (PFIC1) in human or intrahepatic cholestasis in mice. Transmembrane protein 30A (TMEM30A), as a β-subunit, is essential for the function of P4-type ATPases including ATP8B1 and ATP11C, however, its role in the etiology of cholestasis remains poorly understood. To investigate the function of TMEM30A in bile salt homeostasis, we developed Tmem30a liver-specific knockout (LKO) mice. Tmem30a LKO mice suffered from hyperbilirubinaemia, hypercholanaemia, inflammatory infiltration, ductular proliferation and liver fibrosis...
September 14, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28919112/disuse-atrophy-accompanied-by-intramuscular-ectopic-adipogenesis-in-vastus-medialis-muscle-of-advanced-osteoarthritis-patients
#13
Madoka Ikemoto-Uezumi, Yasumoto Matsui, Masaki Hasegawa, Remi Fujita, Yasuhide Kanayama, Akiyoshi Uezumi, Tsuyoshi Watanabe, Atsushi Harada, A Robin Poole, Naohiro Hashimoto
Muscle dysfunction is the most important modifiable mediating factor in primary osteoarthritis because properly contracting muscles are a key absorber of forces acting on a joint. However, the pathological features of disuse muscle atrophy in osteoarthritis patients have been little studied. Vastus medialis muscles of fourteen female patients with osteoarthritis in the age range 69 to 86 years, largely immobile for one or more years, were obtained during arthroplastic surgery and analyzed histologically. These were compared to female patients without arthritis, two with patellar fracture, and two with patellar subluxation...
September 14, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28919111/promethazine-hydrochloride-inhibits-ectopic-fat-cell-formation-in-skeletal-muscle
#14
Takehiro Kasai, Masashi Nakatani, Naoki Ishiguro, Kinji Ohno, Naoki Yamamoto, Mitsuhiro Morita, Harumoto Yamada, Kunihiro Tsuchida, Akiyoshi Uezumi
Fatty degeneration of skeletal muscle leads to muscle weakness and loss of function. Preventing fatty degeneration in skeletal muscle is important, but no drug has been used clinically. In this study, we performed drug repositioning using human platelet-derived growth factor receptor α (PDGFRα)-positive mesenchymal progenitors that have been proved to be an origin of ectopic adipocytes in skeletal muscle. We found that promethazine hydrochloride (PH) inhibits adipogenesis in a dose-dependent manner without cell toxicity...
September 14, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28919110/this-month-in-ajp-november-2017
#15
Chhavi Chauhan
No abstract text is available yet for this article.
September 14, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28919109/long-term-measurements-of-human-inflammatory-cytokines-reveal-complex-baseline-variations-between-individuals
#16
Danlu Wu, Trinh L Dinh, Bruce P Bausk, David R Walt
Comprehensive characterization of the healthy human proteome baseline is essential for personalized medicine. Baseline data are necessary to understand the variation between individuals as well as longitudinal variation within individuals. Many important protein biomarkers, such as cytokines, exist at extremely low or undetectable levels in the healthy state. This paper describes results from a 14-week study of healthy human subjects using ultrasensitive single molecule array (Simoa) assays to measure both intra and intersubject variation of 15 cytokines...
September 14, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28919108/the-renin-angiotensin-system-regulates-neurodegeneration-in-a-mouse-model-of-optic-neuritis
#17
Xiaoli Guo, Kazuhiko Namekata, Atsuko Kimura, Chikako Harada, Takayuki Harada
The major role of the renin-angiotensin system (RAS), including that of angiotensin II (Ang II), the principal effector molecule, in the cardiovascular system is well known. Increasing evidence suggests that the RAS also plays a role in the development of autoimmune diseases. Optic neuritis (ie, inflammation of the optic nerve, with retinal ganglion cell [RGC] loss) is strongly associated with multiple sclerosis (MS). Herein, we investigated the effects of candesartan, an Ang II receptor antagonist, on optic neuritis in experimental autoimmune encephalomyelitis (EAE), an animal model of MS...
September 14, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28919107/combination-of-a%C3%AE-suppression-and-innate-immune-activation-in-the-brain-significantly-attenuates-amyloid-plaque-deposition
#18
Christophe Verbeeck, Anna Carrano, Paramita Chakrabarty, Joanna L Jankowsky, Pritam Das
Anti-Aβ clinical trials are currently underway to determine whether preventing amyloid deposition will be beneficial in arresting progression of Alzheimer disease. Both clinical and pre-clinical studies suggest that anti-amyloid strategies are only effective if started at very early stages of the disease process in a primary prevention strategy. Because this approach will be difficult to deploy, strategies for secondary prevention aimed at later stages of disease are also needed. In this study, we asked whether combining innate immune activation in the brain with concurrent Aβ suppression could enhance plaque clearance and improve pathological outcomes in mice with moderate amyloid pathology...
September 14, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28917668/gut-microbe-mediated-suppression-of-inflammation-associated-colon-carcinogenesis-by-luminal-histamine-production
#19
Chunxu Gao, Bhanu Priya Ganesh, Zhongcheng Shi, Rajesh Rasik Shah, Robert Fultz, Angela Major, Susan Venable, Monica Lugo, Kathleen Hoch, Xiaowei Chen, Anthony Haag, Timothy C Wang, James Versalovic
Microbiome-mediated suppression of carcinogenesis may open new avenues for identification of therapeutic targets and prevention strategies in oncology. Histidine decarboxylase (HDC) deficiency has been shown to promote inflammation-associated colorectal cancer by accumulation of CD11b(+)Gr-1(+) immature myeloid cells, indicating a potential antitumorigenic effect of histamine. Here, we demonstrate that administration of hdc(+)Lactobacillus reuteri in the gut resulted in luminal hdc gene expression and histamine production in the intestines of Hdc(-/-) mice...
September 6, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28837800/systemic-monocyte-chemotactic-protein-1-inhibition-modifies-renal-macrophages-and-restores-glomerular-endothelial-glycocalyx-and-barrier-function-in-diabetic-nephropathy
#20
Margien G S Boels, Angela Koudijs, M Cristina Avramut, Wendy M P J Sol, Gangqi Wang, Annemarie M van Oeveren-Rietdijk, Anton Jan van Zonneveld, Hetty C de Boer, Johan van der Vlag, Cees van Kooten, Dirk Eulberg, Bernard M van den Berg, Daphne H T IJpelaar, Ton J Rabelink
Inhibition of monocyte chemotactic protein-1 (MCP)-1 with the Spiegelmer emapticap pegol (NOX-E36) shows long-lasting albuminuria-reducing effects in diabetic nephropathy. MCP-1 regulates inflammatory cell recruitment and differentiation of macrophages. Since the endothelial glycocalyx is also reduced in diabetic nephropathy, we hypothesized that MCP-1 inhibition restores glomerular barrier function through influencing macrophage cathepsin L secretion, thus reducing activation of the glycocalyx degrading enzyme heparanase...
August 21, 2017: American Journal of Pathology
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