Macrophage-Mediated Phagocytosis and Dissolution of Amyloid-Like Fibrils in Mice, Monitored by Optical Imaging.
Abstract Light chain-associated amyloidosis is characterized by the extracellular deposition of amyloid fibrils in abdominothoracic organs, skin, soft tissue, and peripheral nerves. Phagocytic cells of the innate immune system appear to be ineffective at clearing the material; however, human light chain amyloid extract, injected subcutaneously into mice, is rapidly cleared in a process that requires neutrophil activity. To better elucidate the phagocytosis of light chain fibrils, a potential method of cell-mediated dissolution, amyloid-like fibrils were labeled with the pH-sensitive dye pHrodo red and a near infra...
Source: The American Journal of Pathology - February 5, 2019 Category: Pathology Authors: Richey T, Foster JS, Williams AD, Williams AB, Stroh A, Macy S, Wooliver C, Heidel RE, Varanasi SK, Ergen EN, Trent DJ, Kania SA, Kennel SJ, Martin EB, Wall JS Tags: Am J Pathol Source Type: research

MBD2 inhibits the malignant characteristic of lung adenocarcinoma through the epigenetic modulation of TET1 and mir-200s.
Abstract It has been reported that disorders of epigenetic modulation play a critical role in carcinogenesis. MBD2 is known to act as an epigenetic modulator in various types of tumors; however, the role of MBD2 in lung adenocarcinoma (LUAD) remains unclear. Here, we demonstrated the down-regulation of MBD2 in LUAD compared with adjacent nontumor tissues. The down-regulation of MBD2 in LUAD was correlated with metastasis and poor survival. Additionally, MBD2 inhibited tumor metastasis by maintaining the expression of the mir-200s, which suppressed the invasive properties of tumors. Also, MBD2 positively correlated...
Source: The American Journal of Pathology - February 5, 2019 Category: Pathology Authors: Pei YF, Xu XN, Wang ZF, Wang FW, Wu WD, Geng JF, Liu XQ Tags: Am J Pathol Source Type: research

A Link between the Gut and Bone: Bone Health Impacted by Changes in Gut Microbiota.
Abstract This commentary highlights the article by Hathaway-Schrader et al that studies the impact of antibiotic-disruption of the gut microbiota on long-term bone development. PMID: 30665557 [PubMed - in process] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - January 24, 2019 Category: Pathology Authors: Suva LJ Tags: Am J Pathol Source Type: research

Correction.
Authors: PMID: 30665558 [PubMed - in process] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - January 24, 2019 Category: Pathology Tags: Am J Pathol Source Type: research

Smad3 suppresses epithelial cell migration and proliferation via the clock gene Dec1, which negatively regulates the expression of clock genes Dec2 and Per1.
Abstract Smad3 has circadian expression; however, whether Smad3 affects the expression of clock genes is poorly understood. Here, we investigated the regulatory mechanisms between Smad3 and the clock genes Dec1, Dec2, and Per1. In Smad3 knockout mice, the amplitude of locomotor activity was decreased and Dec1 expression was decreased in the suprachiasmatic nucleus, liver, kidney, and tongue compared with control mice. Conversely, Dec2 and Per1 expression was increased compared with that of control mice. In Smad3 knockout mice, immunohistochemical staining revealed that Dec1 expression decreased, whereas Dec2 and P...
Source: The American Journal of Pathology - January 18, 2019 Category: Pathology Authors: Sato F, Otsuka T, Kohsaka A, Le HT, Bhawal UK, Muragaki Y Tags: Am J Pathol Source Type: research

Impaired Annulus Fibrosis Development and Vertebral Fusion Cause Severe Scoliosis in Mice with Deficiency of JNK1 and JNK2.
er RF Abstract MAP kinases, including JNK, play an important role in the development and function of a large variety of tissues. We analyzed the skeletal phenotype of JNK1 and JNK2 double knockout (dKO) mice (JNK1fl/flCol2-Cre/JNK2-/-) and control genotypes, including single knockouts, at different embryonic and postnatal stages. The JNK1/2 dKO mice displayed a severe scoliotic phenotype that began during development and was grossly apparent around weaning age. Alcian blue staining of embryos (E17.5) showed abnormal fusion of the posterior spinal elements. In the adult mice, fusion of vertebral bodies and of spino...
Source: The American Journal of Pathology - January 18, 2019 Category: Pathology Authors: Ulici V, Kelley KL, Longobardi L, McNulty MA, Livingston EW, Bateman TA, Séguin CA, Louer CR, Loeser RF Tags: Am J Pathol Source Type: research

Sost haploinsufficiency provokes peracute lethal cardiac tamponade without rescuing the osteopenia in a mouse model of excess glucocorticoids.
Abstract Glucocorticoid-induced secondary osteoporosis is the most predictable side-effect of this anti-inflammatory. One of the main mechanisms by which glucocorticoids achieve such deleterious outcome in bone is by antagonizing Wnt/β-catenin signalling. Sclerostin, encoded by Sost gene, is the main negative regulator of the pro-formative and anti-resorptive role of the Wnt signaling pathway in the skeleton. We hypothesized that the partial inactivation of sclerostin function by genetic manipulation will rescue the osteopenia induced by high endogenous glucocorticoid levels. Sost-deficient mice were crossed ...
Source: The American Journal of Pathology - January 18, 2019 Category: Pathology Authors: Javaheri B, Herbert E, Hopkinson M, Al-Jazzar A, Pitsillides AA Tags: Am J Pathol Source Type: research

Spexin/NPQ Induces fos and Produces Antinociceptive Effect against Inflammatory Pain in the Mouse Model.
This study explored the mechanisms and effects of supraspinal spexin on inflammatory pain. The results from the mouse formalin test show that intracerebroventricular (i.c.v.) administration of spexin decreased licking/biting time during the late and early phases. The non-amidated spexin had no effect on pain response. The antinociception of spexin was blocked by galanin receptor 3 antagonist SNAP 37889. The Galr3 and Adcy4 mRNA levels in the brain were increased after injection with spexin. The antinociceptive effects of spexin were completely reversed by opioid receptor antagonist naloxone and κ-opioid receptor anta...
Source: The American Journal of Pathology - January 18, 2019 Category: Pathology Authors: Lv SY, Cui B, Yang Y, Du H, Zhang X, Zhou Y, Ye W, Nie X, Li Y, Wang Q, Chen WD, Wang YD Tags: Am J Pathol Source Type: research

This Month in AJP.
Abstract The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology. PMID: 30659790 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - January 16, 2019 Category: Pathology Authors: Chauhan C Tags: Am J Pathol Source Type: research

Disruption of P2X7 Signaling Increases Susceptibility to Cerebral Toxoplasmosis.
Abstract Toxoplasmosis is a neglected disease that affects millions of individuals worldwide. Toxoplasma gondii infection is an asymptomatic disease, with lethal cases occurring mostly in HIV patients and organ transplant recipients. Nevertheless, atypical strains of T. gondii in endemic locations cause severe pathology in healthy individuals. Toxoplasmosis has no cure but it can be controlled by the pro-inflammatory immune response. The P2X7 purinergic receptor is involved in many inflammatory events and has been associated with genes that confer resistance against toxoplasmosis in humans. In vitro studies report...
Source: The American Journal of Pathology - January 14, 2019 Category: Pathology Authors: Abreu Moreira-Souza AC, Rangel TP, Batista da Silva SR, Figliuolo VR, Baggio Savio LE, Schmitz F, Takiya C, Wyse ATS, Vommaro RC, Coutinho-Silva R Tags: Am J Pathol Source Type: research

Induced Pluripotent Stem Cell-Derived Endothelial Cells: Overview, Current Advances, Applications, And Future Directions.
Abstract Endothelial cells are prevalent in our bodies and serve multiple functions. By lining the vasculature, they provide a barrier to tissues and facilitate the transport of molecules and cells. They also maintain hemostasis and modulate blood flow by reacting to chemokines and releasing signal molecules. Thus, endothelial dysfunction leads to a wide variety of diseases, including atherosclerosis and coronary artery disease. In today's era of stem cell research, induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) have emerged for research and engineering purposes. They are not only tools for stu...
Source: The American Journal of Pathology - January 14, 2019 Category: Pathology Authors: Jang S, Collin de l'Hortet A, Soto-Gutierrez A Tags: Am J Pathol Source Type: research

Liver Regeneration after Acetaminophen Hepatotoxicity: Mechanisms and Therapeutic Opportunities.
Abstract Acetaminophen (APAP) overdose is the most common cause of acute liver failure (ALF) in the western world with limited treatment opportunities. For years, the research on APAP overdose has been focused on investigating mechanisms of hepatotoxicity with limited success in advancing therapeutic strategies. Acute liver injury after any insult, including APAP overdose, is followed by compensatory liver regeneration, which promotes recovery and is a critical determinant of the final outcome. Liver regeneration after APAP-induced liver injury is dose-dependent and impaired after severe APAP overdose. Although ro...
Source: The American Journal of Pathology - January 14, 2019 Category: Pathology Authors: Bhushan B, Apte U Tags: Am J Pathol Source Type: research

Galectin-3 Inhibits Cancer Metastasis by Negatively Regulating Integrin Beta 3 Expression.
Abstract Galectin-3 (Gal-3; gene LGALS3) is a member of the beta-galactose-binding lectin family. Previous studies showed that Gal-3 is expressed in several tissues across species and functions as a regulator of cell proliferation, apoptosis, adhesion, and migration, thus affecting many aspects of events such as angiogenesis and tumorigenesis. Although several reports have suggested that the level of Gal-3 expression correlates positively with tumor progression, here we show that highly metastatic mouse melanoma B16/BL6 cells express less Gal-3 than B16 cells with a lower metastatic potential. It was found that ov...
Source: The American Journal of Pathology - January 14, 2019 Category: Pathology Authors: Hayashi Y, Jia W, Kidoya H, Muramatsu F, Tsukada Y, Takakura N Tags: Am J Pathol Source Type: research

β1 syntrophin supports autophagy initiation and protects against cerulein-induced acute pancreatitis.
β1 syntrophin supports autophagy initiation and protects against cerulein-induced acute pancreatitis. Am J Pathol. 2019 Jan 14;: Authors: Ye R, Onodera T, Blanchard PG, Kusminski CM, Esser V, Brekken RA, Scherer PE Abstract Syntrophins are a family of proteins forming membrane-anchored scaffolds and serving as adaptors for various transmembrane and intracellular signaling molecules. To understand the physiological roles of β1 syntrophin, one of the least characterized members, we generated mouse models to eliminate β1 syntrophin specifically in the endocrine or exocrine pancreas. β...
Source: The American Journal of Pathology - January 14, 2019 Category: Pathology Authors: Ye R, Onodera T, Blanchard PG, Kusminski CM, Esser V, Brekken RA, Scherer PE Tags: Am J Pathol Source Type: research

Leptin Receptor as a Potential Target to Inhibit Human Testicular Seminoma Growth.
Catalano S Abstract Although in the last decades, the adipokine leptin and its own receptor have been considered as significant cancer biomarkers, their potential involvement in human testicular seminoma growth and progression remains unexplored. Here, we demonstrated that the expression of leptin and its receptor was significantly higher in human testicular seminoma compared to normal adult testis. Human seminoma cell line TCam-2 also expressed leptin along with the long and the short isoforms of leptin receptor and in response to leptin treatment, showed an enhanced activation of its downstream effectors. In li...
Source: The American Journal of Pathology - January 2, 2019 Category: Pathology Authors: Panza S, Gelsomino L, Malivindi R, Rago V, Barone I, Giordano C, Giordano F, Leggio A, Comandè A, Liguori A, Aquila S, Bonofiglio D, Andò S, Catalano S Tags: Am J Pathol Source Type: research

Loss of Wnt secretion by macrophages promotes hepatobiliary injury following administration of DDC diet.
In conclusion, this study shows that a lack of macrophage Wnt secretion leads to more DDC-induced hepatic injury due to impaired hepatocyte proliferation and increased M1 macrophages, which promotes immune-mediated cell injury. PMID: 30610845 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - January 2, 2019 Category: Pathology Authors: Jiang A, Okabe H, Popovic B, Preziosi ME, Pradhan-Sundd T, Poddar M, Singh S, Bell A, England SG, Nagarajan S, Monga SP Tags: Am J Pathol Source Type: research

Current Approaches to Pancreatic Cancer Screening.
Abstract Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of only 8% and is estimated to be the second leading cause of cancer-related deaths by 2021. Prior convention held that screening for PDAC would not be beneficial; however, a deeper understanding of the carcinogenesis pathway supports a potential window of opportunity among the target population. Screening for PDAC is not a standard practice among the general population because of its low incidence. However, screening may be beneficial for individuals with familial history, chronic diseases with genetic predispositions, or inherited cancer...
Source: The American Journal of Pathology - December 20, 2018 Category: Pathology Authors: Chhoda A, Lu L, Clerkin BM, Risch H, Farrell JJ Tags: Am J Pathol Source Type: research

Familial Pancreatic Ductal Adenocarcinoma.
Abstract Pancreatic ductal adenocarcinoma (PDAC), although a rare disease, has a poor prognosis. With 5-year overall survival of 8%, there is a critical need to detect PDAC early or at a premalignant stage. Current screening methods are largely imaging based, but a more focused screening approach based on modifiable and nonmodifiable risk factors may improve the efficacy and likely outcomes of screening. In addition, the pathologic mechanisms that lead to the development of PDAC are discussed in an effort to further understand the targets of pancreatic cancer screening. The focus of this article will be inherited ...
Source: The American Journal of Pathology - December 20, 2018 Category: Pathology Authors: Diaz KE, Lucas AL Tags: Am J Pathol Source Type: research

Artificial Intelligence and Pathobiology Join Forces in The American Journal of Pathology.
Abstract This Editorial describes the extension in scope of The American Journal of Pathology. PMID: 30558721 [PubMed - in process] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - December 20, 2018 Category: Pathology Authors: Cohen S, Furie MB Tags: Am J Pathol Source Type: research

The Paradoxical Web of Pancreatic Cancer Tumor Microenvironment.
Abstract Pancreatic ductal adenocarcinoma (PDAC) is increasing in incidence and is projected to become the second leading cause of cancer death in the United States. Despite significant advances in understanding the disease, there has been minimal increase in PDAC patient survival. PDAC tumors are unique in the fact that there is significant desmoplasia. This generates a large stromal compartment composed of immune cells, inflammatory cells, growth factors, extracellular matrix, and fibroblasts, comprising the tumor microenvironment (TME), which may represent anywhere from 15% to 85% of the tumor. It has beco...
Source: The American Journal of Pathology - December 20, 2018 Category: Pathology Authors: Lafaro KJ, Melstrom LG Tags: Am J Pathol Source Type: research

miRNA and Gene Expression in Pancreatic Ductal Adenocarcinoma.
Abstract Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease that is mostly diagnosed late in the course of the illness. Unlike other cancers in which measurable successes have been achieved with traditional chemotherapy, targeted therapy, and, recently, immunotherapy, PDAC has proved to be poorly responsive to these treatments, with only marginal to modest incremental benefits using conventional cytotoxic therapy. There is, therefore, a great unmet need to develop better therapies based on improved understanding of biology and identification of predictive and prognostic biomarkers that would gui...
Source: The American Journal of Pathology - December 20, 2018 Category: Pathology Authors: Tesfaye AA, Azmi AS, Philip PA Tags: Am J Pathol Source Type: research

Pancreatic Ductal Adenocarcinoma: Recent Updates.
Abstract This Guest Editorial introduces this month's special Pancreatic Cancer Theme Issue, a series of reviews intended to highlight the pathologic to molecular profiles and diagnoses of benign and neoplastic pancreatic lesions. PMID: 30558724 [PubMed - in process] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - December 20, 2018 Category: Pathology Authors: Longnecker DS Tags: Am J Pathol Source Type: research

Circulating Tumor Cells and Cell-Free DNA in Pancreatic Ductal Adenocarcinoma.
Abstract Pancreatic cancer is detected late in the disease process and has an extremely poor prognosis. A blood-based biomarker that can enable early detection of disease, monitor response to treatment, and potentially allow for personalized treatment would be of great benefit. This review analyzes the literature regarding two potential biomarkers, circulating tumor cells (CTCs) and cell-free DNA (cfDNA), with regard to pancreatic ductal adenocarcinoma. The origin of CTCs and the methods of detection are discussed and a decade of research examining CTCs in pancreatic cancer is summarized, including both levels of ...
Source: The American Journal of Pathology - December 20, 2018 Category: Pathology Authors: Gall TMH, Belete S, Khanderia E, Frampton AE, Jiao LR Tags: Am J Pathol Source Type: research

Tumefactive Inflammatory Diseases of the Pancreas.
Abstract Advances in the past two decades have resulted in the recognition of several tumefactive pancreatic lesions that, on histologic evaluation, show a varying combination of inflammation and fibrosis. Autoimmune pancreatitis, the prototypic tumefactive pancreatic fibroinflammatory lesion, is composed of two distinct diseases, type 1 autoimmune pancreatitis and the less common type 2 autoimmune pancreatitis. Although designated as autoimmune pancreatitis, the two diseases show little morphologic or pathogenic overlap. In type 1 disease, subsets of T lymphocytes (type 2 helper T cells, regulatory T cells, and T...
Source: The American Journal of Pathology - December 20, 2018 Category: Pathology Authors: Zen Y, Deshpande V Tags: Am J Pathol Source Type: research

Pancreatic Ductal Adenocarcinoma and Its Precursor Lesions: Histopathology, Cytopathology, and Molecular Pathology.
This article reviews clinical features, histopathology, cytopathology, and molecular alterations of pancreatic ductal adenocarcinoma and its precursors. Moreover, we review a recently updated two-tier classification system for precursor lesions, new findings in premalignant cystic neoplasms, and recently updated staging criteria for invasive carcinoma based on the Cancer Staging Manual, eighth edition, from the American Joint Committee on Cancer. Finally, we discuss the potential clinical applications of the rapidly growing molecular and genetic information of pancreatic cancer and its precursors. PMID: 30558727 [PubM...
Source: The American Journal of Pathology - December 20, 2018 Category: Pathology Authors: Ren B, Liu X, Suriawinata AA Tags: Am J Pathol Source Type: research

Expression of Bone Morphogenetic Proteins In Multiple Sclerosis Lesions.
alban X, Espejo C Abstract Bone morphogenetic proteins (BMPs) are secreted proteins that belong to the transforming growth factor-beta superfamily. In the adult brain, they modulate neurogenesis, favor astrogliogenesis, and inhibit oligodendrogenesis. As BMPs may be involved in the failure of remyelination in multiple sclerosis (MS), we characterized the expression of BMP-2, -4, -5, and -7; BMP type II receptor (BMPRII); and phosphorylated (p)SMAD 1/5/8 in lesions of MS and other demyelinating diseases. Forty-two MS lesions, 12 acute ischemic lesions, eight progressive multifocal leucoencephalopathy lesions, and 1...
Source: The American Journal of Pathology - December 13, 2018 Category: Pathology Authors: Costa C, Eixarch H, Martínez-Sáez E, Calvo-Barreiro L, Calucho M, Castro Z, Ortega-Aznar A, Ramón Y Cajal S, Montalban X, Espejo C Tags: Am J Pathol Source Type: research

LINE-1 retrotransposons become deregulated during the development of ovarian cancer precursor lesions.
In this study, we assessed LINE-1 open reading frame 1 protein expression in 12 p53 signature lesions, 32 STICs, and 112 various types of ovarian cancers via immunohistochemical staining and examined LINE-1 promoter methylation in representative cases. We found that 78% and 57% of STICs, with and without concurrent ovarian carcinomas, respectively, exhibited intense LINE-1 immunoreactivity compared to adjacent, normal-appearing fallopian tube epithelium. Hypomethylation of the LINE-1 promoter was found in all STICs exhibiting overexpression. None of the 12 p53 signatures demonstrated significant LINE-1 expression. In ovari...
Source: The American Journal of Pathology - December 13, 2018 Category: Pathology Authors: Pisanic TR, Asaka S, Lin SF, Yen TT, Sun H, Bahadirli-Talbott A, Wang TH, Burns KH, Wang TL, Shih IM Tags: Am J Pathol Source Type: research

Dynamin-1-like protein inhibition drives megamitochondria formation as an adaptive response in alcohol-induced hepatotoxicity.
In this study, we investigated the mitochondrial and cellular response to alcohol in hepatoma cell line VL-17A. The mitochondrial architecture rapidly changed after 3 or 14 days of ethanol exposure with double-pronged presentation of hyper-fragmentation and megamitochondria and cell growth was inhibited. Dynamin-1-like protein (Drp1) was identified as the main mediator driving these mitochondrial alterations and its genetic inactivation was determined to foster megamitochondria development, preserving the capacity of the cells to grow despite alcohol toxicity. The role of Drp1 in mediating megamitochondria formation in mic...
Source: The American Journal of Pathology - December 13, 2018 Category: Pathology Authors: Palma E, Ma X, Riva A, Iansante V, Dhawan A, Wang S, Ni HM, Sesaki H, Williams R, Ding WX, Chokshi S Tags: Am J Pathol Source Type: research

Heparan Sulfate Proteoglycan Synthesis is Dysregulated in Human Osteoarthritic Cartilage.
Abstract Osteoarthritis (OA) is a common degenerative joint disease, characterized by cartilage loss and subchondral bone remodelling in response to abnormal mechanical load. Heparan sulfate (HS) proteoglycans bind to many proteins that regulate cartilage homeostasis, including growth factors, morphogens, proteases, and their inhibitors, and modulate their localization, retention, and biological activity. Changes in HS expression and structure may thus have important consequences for joint health. We analyzed normal and osteoarthritic human knee cartilage, and found HS biosynthesis was markedly disrupted in OA, wi...
Source: The American Journal of Pathology - December 13, 2018 Category: Pathology Authors: Chanalaris A, Clarke H, Guimond SE, Vincent TL, Turnbull JE, Troeberg L Tags: Am J Pathol Source Type: research

Ganglioside synthase knock-out reduces prion disease incubation time in mouse models.
Abstract Localization of the abnormal and normal isoforms of prion proteins to detergent-resistant membrane microdomains, lipid rafts, is important for the conformational conversion. Lipid rafts are enriched in sialic acid-containing glycosphingolipids, namely gangliosides. Alteration in the ganglioside composition of lipid rafts can affect the localization of lipid raft-associated proteins. To investigate the role of gangliosides in the pathogenesis of prion diseases, we performed intracerebral transmission study of a scrapie prion strain Chandler and a Gerstmann-Sträussler-Scheinker syndrome prion strain Fu...
Source: The American Journal of Pathology - December 13, 2018 Category: Pathology Authors: Kobayashi A, Qi Z, Shimazaki T, Munesue Y, Miyamoto T, Isoda N, Sawa H, Aoshima K, Kimura T, Mohri S, Kitamoto T, Yamashita T, Miyoshi I Tags: Am J Pathol Source Type: research

Augmenter of liver regeneration protects against ethanol-induced acute liver injury by promoting autophagy.
Abstract Alcoholic liver disease is associated with high morbidity and mortality, and treatment options are limited to date. Augmenter of liver regeneration (ALR) may protect against hepatic injury caused by chemical poisons, including ethanol. Autophagy appears to positively influence survival in cases of liver dysfunction, though the mechanisms are poorly understood. Here, we investigated the impact of ALR-induced autophagy in vitro and in vivo in an ethanol-induced model of acute liver injury. Decreased serum levels of alanine aminotransferase and aspartate aminotransferase and reduced histological lesions reve...
Source: The American Journal of Pathology - December 13, 2018 Category: Pathology Authors: Liu L, Xie P, Li W, Wu Y, An W Tags: Am J Pathol Source Type: research

Podocytes: Way to go.
Abstract This commentary highlights the article by Hara et al that discusses the clinical implications of mitotic catastrophe in podocyte health during diabetic kidney disease. PMID: 30543788 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - December 10, 2018 Category: Pathology Authors: Altintas MM, Reiser J Tags: Am J Pathol Source Type: research

This Month in AJP.
PMID: 30543789 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - December 10, 2018 Category: Pathology Authors: Chauhan C Tags: Am J Pathol Source Type: research

Antibiotic-Induced Dysbiosis of Gut Microbiota Impairs Corneal Nerve Regeneration by Affecting CCR2-Negative Macrophage Distribution.
This study also indicates the potential of probiotics as a therapeutic strategy for promoting the regeneration of damaged corneal nerve fibers when the gut microbiota is in dysbiosis. PMID: 30470496 [PubMed - in process] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - November 25, 2018 Category: Pathology Authors: Liu J, Wu M, He J, Xiao C, Xue Y, Fu T, Lin C, Dong D, Li Z Tags: Am J Pathol Source Type: research

This Month in AJP.
Authors: Abstract The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology. PMID: 30448199 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - November 15, 2018 Category: Pathology Tags: Am J Pathol Source Type: research

Inflammatory stress causes N-glycan processing deficiency in ocular autoimmune disease.
o P Abstract High levels of proinflammatory cytokines have been associated with loss of tissue function in ocular autoimmune diseases but the basis for this relationship remains poorly understood. Here we investigated a new role for tumor necrosis factor (TNF)-α in promoting N-glycan processing deficiency at the surface of the eye through inhibition of N-acetylglucosaminyltransferase expression in the Golgi. Using mass spectrometry, complex-type biantennary oligosaccharides were identified as major N-glycan structures in differentiated human corneal epithelial cells. Remarkably, significant differences were ...
Source: The American Journal of Pathology - November 15, 2018 Category: Pathology Authors: Woodward AM, Lehoux S, Mantelli F, Di Zazzo A, Brockhausen I, Bonini S, Argüeso P Tags: Am J Pathol Source Type: research

Tyrosinase is a novel endogenous regulator of developmental and inflammatory lymphangiogenesis.
n C Abstract Lymphangiogenesis is critically involved in tissue fluid balance, graft rejection, and tumor metastasis. Endogenous regulation of lymphangiogenesis is poorly understood. Here we use the lymphatic vessel architecture at the limbal border of the normally avascular cornea, a quantitative trait under strong genetic influence, as a model system to identify new candidate genes regulating lymphangiogenesis. Comparing low-lymphangiogenic BALB/cN versus high-lymphangiogenic C57BL/6N mice, we performed quantitative trait loci analysis of five phenotypes in a large BALB/cN x C57BL/6N intercross (n=795) and ident...
Source: The American Journal of Pathology - November 15, 2018 Category: Pathology Authors: Büttner C, Clahsen T, Regenfuss B, Dreisow ML, Steiber Z, Bock F, Reis A, Cursiefen C Tags: Am J Pathol Source Type: research

Retinal Vascular Abnormalities and Microglia Activation in Mice with Deficiency in CYP46A1-Mediated Cholesterol Removal.
Abstract CYP46A1 is the cytochrome P450 enzyme that converts cholesterol to 24-hydroxycholesterol, a cholesterol elimination product and a potent liver X receptor (LXR) ligand. We conducted retinal characterizations of Cyp46a1-/- mice that had normal fasting blood glucose levels but up to 1.8-fold increase in retinal cholesterol. The retina of Cyp46a1-/- mice exhibited venous beading and tortuosity, microglia/macrophage activation, and increased vascular permeability, features commonly associated with diabetic retinopathy. The expression of Lxrα and Lxrβ was increased in both the whole Cyp46a1-/- retina...
Source: The American Journal of Pathology - November 15, 2018 Category: Pathology Authors: Saadane A, Mast N, Trichonas G, Chakraborty D, Hammer S, Busik JV, Grant MB, Pikuleva IA Tags: Am J Pathol Source Type: research

Fibrosis rescue improves cardiac function in dystrophin-deficient mice and Duchenne patient-specific cardiomyocytes by immunoproteasome modulation.
Abstract Patients affected by Duchenne muscular dystrophy (DMD) develop a progressive dilated cardiomyopathy characterized by inflammatory cell infiltration, necrosis, and cardiac fibrosis. Standard treatments consider the use of β-blockers and angiotensin-converting enzyme inhibitors that are symptomatic and unspecific towards DMD disease. Medications that target DMD cardiac fibrosis are in early stages of development. Here, we demonstrated immunoproteasome dysregulation in affected hearts of mdx mice (murine animal model of DMD) and cardiomyocytes derived from induced pluripotent stem cells of DMD patients....
Source: The American Journal of Pathology - November 15, 2018 Category: Pathology Authors: Farini A, Gowran A, Bella P, Sitzia C, Scopece A, Castiglioni E, Rovina D, Nigro P, Villa C, Fortunato F, Comi GP, Milano G, Pompilio G, Torrente Y Tags: Am J Pathol Source Type: research

Hepatocyte PPAR α enhances liver regeneration after partial hepatectomy in mice.
Hepatocyte PPARα enhances liver regeneration after partial hepatectomy in mice. Am J Pathol. 2018 Nov 15;: Authors: Xie G, Yin S, Zhang ZZ, Qi D, Wang X, Kim D, Yagai T, Brocker CN, Wang Y, Gonzalez FJ, Wang H, Qu A Abstract Peroxisome proliferator-activated receptor α (PPARα) is a key nuclear receptor involved in the control of lipid homeostasis. In rodents, PPARα is also a potent hepaticmitogen. Hepatocyte-specific disruption of PPARα inhibits agonist-induced hepatocyte proliferation; however, little is known about the exact role of PPARα in partial hepatectomy (P...
Source: The American Journal of Pathology - November 15, 2018 Category: Pathology Authors: Xie G, Yin S, Zhang ZZ, Qi D, Wang X, Kim D, Yagai T, Brocker CN, Wang Y, Gonzalez FJ, Wang H, Qu A Tags: Am J Pathol Source Type: research

Role of endoplasmic reticulum stress in pro-inflammatory cytokine-mediated inhibition of trophoblast invasion in placenta-related complications of pregnancy.
This study provides the first mechanistic linkage by which pro-inflammatory cytokines may modulate trophoblast invasion through ER stress pathways. PMID: 30448406 [PubMed - as supplied by publisher] (Source: The American Journal of Pathology)
Source: The American Journal of Pathology - November 15, 2018 Category: Pathology Authors: Lee CL, Veerbeek JHW, Rana TK, van Rijn BB, Burton GJ, Yung HW Tags: Am J Pathol Source Type: research

Elevated membrane cholesterol disrupts lysosomal degradation to induce A β accumulation: the potential mechanism underlying augmentation of Aβ pathology by type 2 diabetes mellitus.
Elevated membrane cholesterol disrupts lysosomal degradation to induce Aβ accumulation: the potential mechanism underlying augmentation of Aβ pathology by type 2 diabetes mellitus. Am J Pathol. 2018 Nov 15;: Authors: Takeuchi S, Ueda N, Suzuki K, Shimozawa N, Yasutomi Y, Kimura N Abstract Endocytic membrane trafficking system is altered in the brains of early-stage Alzheimer disease (AD) patients, and endocytic disturbance affects the metabolism of β-amyloid protein (Aβ), a key molecule in AD pathogenesis. It is widely accepted that type 2 diabetes mellitus (T2DM) is one of the str...
Source: The American Journal of Pathology - November 15, 2018 Category: Pathology Authors: Takeuchi S, Ueda N, Suzuki K, Shimozawa N, Yasutomi Y, Kimura N Tags: Am J Pathol Source Type: research

The atypical chemokine receptor 2 limits progressive fibrosis after acute ischemic kidney injury.
hauer V Abstract Following renal ischemia-reperfusion injury (IRI) resolution of inflammation allows tubular regeneration, whereas ongoing inflammatory injury mediated by infiltrating leukocytes leads to nephron loss and renal fibrosis, typical hallmarks of chronic kidney disease. The atypical chemokine receptor 2 (ACKR2) is a chemokine decoy receptor, that binds and scavenges inflammatory CC-chemokines and reduces local leukocyte accumulation. We hypothesized that ACKR2 limits leukocyte infiltration, inflammation, and fibrotic tissue remodeling after renal IRI, thus preventing progression to chronic kidney diseas...
Source: The American Journal of Pathology - November 15, 2018 Category: Pathology Authors: Lux M, Blaut A, Eltrich N, Bideak A, Müller MB, Hoppe JM, Gröne HJ, Locati M, Vielhauer V Tags: Am J Pathol Source Type: research

Loss of integrin αvβ8 in murine hepatocytes accelerates liver regeneration.
Loss of integrin αvβ8 in murine hepatocytes accelerates liver regeneration. Am J Pathol. 2018 Nov 15;: Authors: Greenhalgh SN, Matchett KP, Taylor RS, Huang K, Li JT, Saeteurn K, Donnelly MC, Simpson EE, Pollack JL, Atakilit A, Simpson KJ, Maher JJ, Iredale JP, Sheppard D, Henderson NC Abstract Recent fate-mapping studies in mice have provided substantial evidence that mature adult hepatocytes are a major source of new hepatocytes following liver injury. In other systems, integrin αvβ8 has a major role in activating transforming growth factor beta (TGFβ), a potent inhibitor ...
Source: The American Journal of Pathology - November 15, 2018 Category: Pathology Authors: Greenhalgh SN, Matchett KP, Taylor RS, Huang K, Li JT, Saeteurn K, Donnelly MC, Simpson EE, Pollack JL, Atakilit A, Simpson KJ, Maher JJ, Iredale JP, Sheppard D, Henderson NC Tags: Am J Pathol Source Type: research

The danger signal extracellular ATP is involved in the immuno-mediated damage of alpha-sarcoglycan deficient muscular dystrophy.
Abstract In muscular dystrophies the muscle membrane fragility results in a tissue-specific increase of danger-associated molecules (DAMPs) and infiltration of inflammatory cells. The DAMP extracellular adenosine triphosphate (eATP) released by dying myofibers steadily activates muscle and immune purinergic receptors exerting dual negative effects: a direct damage linked to altered intracellular calcium homeostasis in muscle cells and an indirect toxicity through the "triggering" of the immune response and inhibition of regulatory T cells. Accordingly, pharmacological and genetic inhibition of eATP signa...
Source: The American Journal of Pathology - November 15, 2018 Category: Pathology Authors: Gazzerro E, Baratto S, Assereto S, Baldassari S, Panicucci C, Raffaghello L, Scudieri P, De Battista D, Fiorillo C, Volpi S, Chaabane L, Malnati M, Messina G, Bruzzone S, Traggiai E, Grassi F, Minetti C, Bruno C Tags: Am J Pathol Source Type: research

A Novel Transgenic Rat Model of Robust Cerebral Microvascular Amyloid with Prominent Vasculopathy.
Abstract Accumulation of fibrillar amyloid β protein in blood vessels of the brain, a condition known as cerebral amyloid angiopathy (CAA), is a common pathology of elderly individuals, a prominent comorbidity of Alzheimer disease, and a driver of vascular cognitive impairment and dementia. Although several transgenic mouse strains have been generated that develop varying levels of CAA, consistent models of associated cerebral microhemorrhage and vasculopathy observed clinically have been lacking. Reliable preclinical animal models of CAA and microhemorrhage are needed to investigate the molecular pathogenesi...
Source: The American Journal of Pathology - November 10, 2018 Category: Pathology Authors: Davis J, Xu F, Hatfield J, Lee H, Hoos MD, Popescu D, Crooks E, Kim R, Smith SO, Robinson JK, Benveniste H, Van Nostrand WE Tags: Am J Pathol Source Type: research

The Accumulation of Heparan Sulfate S-Domains in Kidney Transthyretin Deposits Accelerates Fibril Formation and Promotes Cytotoxicity.
Abstract The highly sulfated domains of heparan sulfate (HS), also called HS S-domains, are made up of repeated trisulfated disaccharide units [iduronic acid (2S)-glucosamine (NS, 6S)-] and are selectively remodeled by extracellular endoglucosamine 6-sulfatases (Sulfs). Although HS S-domains are critical for signal transduction of several growth factors, their roles in amyloidoses are not yet fully understood. Here, we found HS S-domains in the kidney of a patient with transthyretin amyloidosis (ATTR amyloidosis). In in vitro assays with cells stably expressing human Sulfs, heparin, a structural analog of HS S-dom...
Source: The American Journal of Pathology - November 7, 2018 Category: Pathology Authors: Kameyama H, Uchimura K, Yamashita T, Kuwabara K, Mizuguchi M, Hung SC, Okuhira K, Masuda T, Kosugi T, Ohgita T, Saito H, Ando Y, Nishitsuji K Tags: Am J Pathol Source Type: research

Pseudoxanthoma Elasticum as a Paradigm of Heritable Ectopic Mineralization Disorders: Pathomechanisms and Treatment Development.
Abstract Ectopic mineralization is a global problem and leading cause of morbidity and mortality. The pathomechanisms of ectopic mineralization are poorly understood. Recent studies on heritable ectopic mineralization disorders with defined gene defects have been helpful in elucidation of the mechanisms of ectopic mineralization in general. The prototype of such disorders is pseudoxanthoma elasticum (PXE), a late-onset, slowly progressing disorder with multi-system clinical manifestations. Other conditions include generalized arterial calcification of infancy (GACI) characterized by severe, early-onset mineralizat...
Source: The American Journal of Pathology - November 7, 2018 Category: Pathology Authors: Li Q, van de Wetering K, Uitto J Tags: Am J Pathol Source Type: research

Nur77: Key Functions and Therapeutic Prospects in Inflammation-Related Lung Diseases.
Abstract The transcription factor nuclear receptor 77 (Nur77) belongs to the NR4A subfamily of nuclear hormone receptors. It features an atypical ligand-binding site that precludes canonical ligand binding, leading to the designation "orphan nuclear receptor." However, recent studies show that small molecules can interact with the receptor and modulate its activity by inducing a conformational change in the Nur77 ligand-binding site. Nur77 expression and activation are rapidly induced by a wide range of physiological and pathological stimuli. Once expressed, Nur77 initiates transcriptional activity and m...
Source: The American Journal of Pathology - November 7, 2018 Category: Pathology Authors: Banno A, Lakshmi SP, Reddy AT, Kim SC, Reddy RC Tags: Am J Pathol Source Type: research

Adult Hepatocytes Are Hedgehog-Responsive Cells in the Setting of Liver Injury: Evidence for Smoothened-Mediated Activation of NF- κB/Epidermal Growth Factor Receptor/Akt in Hepatocytes that Counteract Fas-Induced Apoptosis.
Adult Hepatocytes Are Hedgehog-Responsive Cells in the Setting of Liver Injury: Evidence for Smoothened-Mediated Activation of NF-κB/Epidermal Growth Factor Receptor/Akt in Hepatocytes that Counteract Fas-Induced Apoptosis. Am J Pathol. 2018 Nov;188(11):2605-2616 Authors: Wang Y, Chen W, Han C, Zhang J, Song K, Kwon H, Dash S, Yao L, Wu T Abstract Although hedgehog (Hh) signaling pathway is inactive in adult healthy liver, it becomes activated during acute and chronic liver injury and, thus, modulates the reparative process and disease progression. We developed a novel mouse model with liver-spe...
Source: The American Journal of Pathology - October 28, 2018 Category: Pathology Authors: Wang Y, Chen W, Han C, Zhang J, Song K, Kwon H, Dash S, Yao L, Wu T Tags: Am J Pathol Source Type: research