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The role of angiotensin II in parietal epithelial cell proliferation and crescent formation in glomerular diseases.
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The role of angiotensin II in parietal epithelial cell proliferation and crescent formation in glomerular diseases.

Am J Pathol. 2017 Aug 11;:

Authors: Rizzo P, Novelli R, Rota C, Gagliardini E, Ruggiero B, Rottoli D, Benigni A, Remuzzi G

Abstract
Crescentic glomerulonephritis (GN) is a devastating disease with rapidly progressive deterioration in kidney function, which, histologically, manifests as crescent formation in most glomeruli. We previously found that crescents derive from the aberrant proliferation and migration of parietal epithelial cells (PECs)/progenitor cells, and that the angiotensin (ang) II/ang II type-1 (AT1) receptor pathway may participate, together with the stromal cell-derived factor-1 (SDF-1)/CXCR4 axis, in the development of those lesions. Here, we elucidated sequential events and cellular and molecular interactions occurring during crescentic lesion onset and evolution. By analyzing kidney biopsies of patients with extracapillary GN, divided according to the grade of glomerular lesions, we found that the accumulation of macrophages expressing matrix metallopeptidase-12 started manifesting in glomeruli affected by early stage lesions, whereas AT1 receptor expression could not be detected. In glomeruli with advanced lesions, AT1 receptor expression increased markedly, and the up-regulation of SDF-1, and its receptor CXCR7, was documented on podocytes and PECs, respectively. In vitro studies were instrumental to demonstrating the role of ang II in inducing podocyte SDF-1 production, which ultimately activates PECs. The present findings support the possibility that angiotensin-converting enzyme inhibitor treatment might limit PEC activation and reduce the frequency and extension of crescents in extracapillary GN.

PMID: 28807596 [PubMed - as supplied by publisher]




Sphingosine kinase-2 deficiency ameliorates kidney fibrosis by up-regulating Smad7 in a mouse model of unilateral ureteral obstruction.
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Sphingosine kinase-2 deficiency ameliorates kidney fibrosis by up-regulating Smad7 in a mouse model of unilateral ureteral obstruction.

Am J Pathol. 2017 Aug 11;:

Authors: Schwalm S, Beyer S, Frey H, Haceni R, Grammatikos G, Thomas D, Geisslinger G, Schaefer L, Huwiler A, Pfeilschifter J

Abstract
Kidney fibrosis is a hallmark of chronic kidney disease and leads to extracellular matrix accumulation, organ scarring, and loss of kidney function. In this study, we investigated the role of sphingosine kinase-2 (SPHK2) on the progression of tubular fibrosis by utilizing a mouse unilateral ureteral obstruction (UUO) model. We found that SPHK2 protein and activity are up-regulated in fibrotic renal tissue. Functionally, Sphk2 deficient (Sphk2(-/-)) mice showed an attenuated fibrotic response to UUO compared to wild-type mice as demonstrated by reduced collagen abundance and decreased expression of fibronectin-1, collagen I, α-smooth muscle actin, connective tissue growth factor (CTGF), and plasminogen activator inhibitor (PAI-1). Importantly, these changes were associated with increased expression of the antifibrotic protein Smad7 and higher levels of sphingosine in Sphk2(-/-) UUO kidneys. Mechanistically, sphingosine ameliorates transforming growth factor- β-induced collagen accumulation, CTGF, and PAI-1 expression, but enhances Smad7 protein expression in primary kidney fibroblasts. In a complementary approach, in human Sphk2-overexpressing mice, UUO resulted in exacerbated signs of fibrosis with increased collagen accumulation, higher expression levels of fibronectin-1, collagen I, α-smooth muscle actin, CTGF, and PAI-1 but decreased Smad7 expression. SPHK2 plays an important role in kidney fibrogenesis by modulating transforming growth factor-β signaling. Thus, SPHK2 might be an attractive new target for the treatment of fibrosis in chronic kidney disease.

PMID: 28807595 [PubMed - as supplied by publisher]




Thyroid hormone receptor-beta agonist GC-1 inhibits Met-β-catenin driven hepatocellular cancer.
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Thyroid hormone receptor-beta agonist GC-1 inhibits Met-β-catenin driven hepatocellular cancer.

Am J Pathol. 2017 Aug 11;:

Authors: Puliga E, Min Q, Tao J, Zhang R, Pradhan-Sundd T, Poddar M, Singh S, Columbano A, Yu J, Monga SP

Abstract
The thyromimetic agent GC-1 induces hepatocyte proliferation via Wnt/β-catenin signaling and may promoting regeneration in both acute and chronic liver insufficiencies. However, β-catenin activation particularly due to mutations in CTNNB1 is seen in a subset of hepatocellular carcinomas (HCC). Thus, it will be critical to address any effect of GC-1 on HCC growth and development, before its use can be advocated to stimulate regeneration in chronic liver diseases. In the current study, we first examine the effect of GC-1 on β-catenin-TCF4 activity in HCC cell lines harboring wild-type or mutated-CTNNB1. Next, we assess the effect of GC-1 on HCC in FVB mice generated by hydrodynamic tail vein injection of hMet-S45Y-β-catenin, using the sleeping beauty transposon-transposase. Four weeks following injection, mice were fed GC-1- (5mg/kg) or basal-diet for 10 or 21 days. GC-1 treatment showed no effect on β-catenin-TCF4 activity in HCC cells, irrespective of CTNNB1 mutations. Treatment with GC-1 for 10 or 21 days led to a significant reduction in tumor burden, associated with decreased tumor cell proliferation, and dramatic decreases in p-Met (Y1234/1235) p-ERK and p-STAT3 without affecting β-catenin and its downstream targets.
CONCLUSION: GC-1 exerts a notable antitumoral effect on hMet-S45Y-β-catenin HCC, by inactivating Met signaling. GC-1 does not promote β-catenin activation in HCC. Thus GC-1 may be safe for use in inducing regeneration during chronic hepatic insufficiency.

PMID: 28807594 [PubMed - as supplied by publisher]




Inflammation and Lymphedema Are Exacerbated and Prolonged by Neuropilin 2 Deficiency.
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Inflammation and Lymphedema Are Exacerbated and Prolonged by Neuropilin 2 Deficiency.

Am J Pathol. 2016 Nov;186(11):2803-2812

Authors: Mucka P, Levonyak N, Geretti E, Zwaans BM, Li X, Adini I, Klagsbrun M, Adam RM, Bielenberg DR

Abstract
The vasculature influences the progression and resolution of tissue inflammation. Capillaries express vascular endothelial growth factor (VEGF) receptors, including neuropilins (NRPs), which regulate interstitial fluid flow. NRP2, a receptor of VEGFA and semaphorin (SEMA) 3F ligands, is expressed in the vascular and lymphatic endothelia. Previous studies have demonstrated that blocking VEGF receptor 2 attenuates VEGFA-induced vascular permeability. The inhibition of NRP2 was hypothesized to decrease vascular permeability as well. Unexpectedly, massive tissue swelling and edema were observed in Nrp2(-/-) mice compared with wild-type littermates after delayed-type hypersensitivity reactions. Vascular permeability was twofold greater in inflamed blood vessels in Nrp2-deficient mice compared to those in Nrp2-intact littermates. The addition of exogenous SEMA3F protein inhibited vascular permeability in Balb/cJ mice, suggesting that the loss of endogenous Sema3F activity in the Nrp2-deficient mice was responsible for the enhanced vessel leakage. Functional lymphatic capillaries are necessary for draining excess fluid after inflammation; however, Nrp2-mutant mice lacked superficial lymphatic capillaries, leading to 2.5-fold greater fluid retention and severe lymphedema after inflammation. In conclusion, Nrp2 deficiency increased blood vessel permeability and decreased lymphatic vessel drainage during inflammation, highlighting the importance of the NRP2/SEMA3F pathway in the modulation of tissue swelling and resolution of postinflammatory edema.

PMID: 27751443 [PubMed - indexed for MEDLINE]




Neuropeptide Y as a Biomarker and Therapeutic Target for Neuroblastoma.
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Neuropeptide Y as a Biomarker and Therapeutic Target for Neuroblastoma.

Am J Pathol. 2016 Nov;186(11):3040-3053

Authors: Galli S, Naranjo A, Van Ryn C, Tilan JU, Trinh E, Yang C, Tsuei J, Hong SH, Wang H, Izycka-Swieszewska E, Lee YC, Rodriguez OC, Albanese C, Kitlinska J

Abstract
Neuroblastoma (NB) is a pediatric malignant neoplasm of sympathoadrenal origin. Challenges in its management include stratification of this heterogeneous disease and a lack of both adequate treatments for high-risk patients and noninvasive biomarkers of disease progression. Our previous studies have identified neuropeptide Y (NPY), a sympathetic neurotransmitter expressed in NB, as a potential therapeutic target for these tumors by virtue of its Y5 receptor (Y5R)-mediated chemoresistance and Y2 receptor (Y2R)-mediated proliferative and angiogenic activities. The goal of this study was to determine the clinical relevance and utility of these findings. Expression of NPY and its receptors was evaluated in corresponding samples of tumor RNA, tissues, and sera from 87 patients with neuroblastic tumors and in tumor tissues from the TH-MYCN NB mouse model. Elevated serum NPY levels correlated with an adverse clinical presentation, poor survival, metastasis, and relapse, whereas strong Y5R immunoreactivity was a marker of angioinvasive tumor cells. In NB tissues from TH-MYCN mice, high immunoreactivity of both NPY and Y5R marked angioinvasive NB cells. Y2R was uniformly expressed in undifferentiated tumor cells, which supports its previously reported role in NB cell proliferation. Our findings validate NPY as a therapeutic target for advanced NB and implicate the NPY/Y5R axis in disease dissemination. The correlation between elevated systemic NPY and NB progression identifies serum NPY as a novel NB biomarker.

PMID: 27743558 [PubMed - indexed for MEDLINE]




CXCL1-Chemokine (C-X-C Motif) Receptor 2 Signaling Stimulates the Recruitment of Bone Marrow-Derived Mesenchymal Cells into Diffuse-Type Gastric Cancer Stroma.
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CXCL1-Chemokine (C-X-C Motif) Receptor 2 Signaling Stimulates the Recruitment of Bone Marrow-Derived Mesenchymal Cells into Diffuse-Type Gastric Cancer Stroma.

Am J Pathol. 2016 Nov;186(11):3028-3039

Authors: Kasashima H, Yashiro M, Nakamae H, Kitayama K, Masuda G, Kinoshita H, Fukuoka T, Hasegawa T, Nakane T, Hino M, Hirakawa K, Ohira M

Abstract
Tumor stromal cells play a critical role in the progression of diffuse-type gastric cancer (DGC). The aim of this study was to clarify where tumor stromal cells originate from and which factor(s) recruits them into the tumor stroma. Immunodeficient mice with bone marrow transplantation from the cytomegalovirus enhancer/chicken β-actin promoter-enhanced green fluorescent protein mice were used for the in vivo experiments. An in vitro study analyzed the chemotaxis-stimulating factor from DGC cells using bone marrow-derived mesenchymal cells (BM-MCs). The influences of chemokine (C-X-C motif) receptor 2 (CXCR2) inhibitor on the migration of BM-MCs were examined both in vitro and in vivo. BM-MCs frequently migrated into stroma of DGC in vivo. The number of migrating BM-MCs was increased by conditioned medium from DGC cells. CXCL1 from DGC cells stimulated the chemoattractant ability of BM-MCs. Both anti-CXCL1 antibody and CXCR2 inhibitor decreased the migration of BM-MCs, stimulated by DGC cells. A CXCR2 inhibitor, SB225002, reduced the recruitment of BM-MCs into the tumor microenvironment in vivo, decreasing tumor size and lymph node metastasis, and prolonging the survival of gastric tumor-bearing mice. These findings suggested that most tumor stromal cells in DGC might originate from BM-MCs. CXCL1 from DGC cells stimulates the recruitment of BM-MCs into tumor stroma via CXCR2 signaling of BM-MCs. Inhibition of BM-MC recruitment via the CXCL1-CXCR2 axis appears a promising therapy for DGC.

PMID: 27742059 [PubMed - indexed for MEDLINE]




Fibromodulin Is Essential for Fetal-Type Scarless Cutaneous Wound Healing.
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Fibromodulin Is Essential for Fetal-Type Scarless Cutaneous Wound Healing.

Am J Pathol. 2016 Nov;186(11):2824-2832

Authors: Zheng Z, Zhang X, Dang C, Beanes S, Chang GX, Chen Y, Li CS, Lee KS, Ting K, Soo C

Abstract
In contrast to adult and late-gestation fetal skin wounds, which heal with scar, early-gestation fetal skin wounds display a remarkable capacity to heal scarlessly. Although the underlying mechanism of this transition from fetal-type scarless healing to adult-type healing with scar has been actively investigated for decades, in utero restoration of scarless healing in late-gestation fetal wounds has not been reported. In this study, using loss- and gain-of-function rodent fetal wound models, we identified that fibromodulin (Fm) is essential for fetal-type scarless wound healing. In particular, we found that loss of Fm can eliminate the ability of early-gestation fetal rodents to heal without scar. Meanwhile, administration of fibromodulin protein (FM) alone was capable of restoring scarless healing in late-gestation rat fetal wounds, which naturally heal with scar, as characterized by dermal appendage restoration and organized collagen architectures that were virtually indistinguishable from those in age-matched unwounded skin. High Fm levels correlated with decreased transforming growth factor (TGF)-β1 expression and scarless repair, while low Fm levels correlated with increased TGF-β1 expression and scar formation. This study represents the first successful in utero attempt to induce scarless repair in late-gestation fetal wounds by using a single protein, Fm, and highlights the crucial role that the FM-TGF-β1 nexus plays in fetal-type scarless skin repair.

PMID: 27665369 [PubMed - indexed for MEDLINE]




Future Perspectives on Pathogenesis of Lupus Nephritis: Facts, Problems, and Potential Causal Therapy Modalities.
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Future Perspectives on Pathogenesis of Lupus Nephritis: Facts, Problems, and Potential Causal Therapy Modalities.

Am J Pathol. 2016 Nov;186(11):2772-2782

Authors: Rekvig OP, Thiyagarajan D, Pedersen HL, Horvei KD, Seredkina N

Abstract
Divergent incommensurable models have been developed to explain the pathogenesis of lupus nephritis. Most contemporary models favor a central role for anti-chromatin antibodies. How they exert their pathogenic effect has, however, endorsed conflicts that at least for now preclude insight into definitive pathogenic pathways. The following paradigms are contemporarily in conflict with each other: i) the impact of anti-double-stranded DNA (dsDNA) antibodies that cross-react with inherent renal antigens, ii) the impact of anti-dsDNA antibodies targeting exposed chromatin in glomeruli, and iii) the impact of relative antibody avidity for dsDNA, chromatin fragments, or cross-reacting antigens. Aside from these three themes, the pathogenic role of T cells in lupus nephritis is not clear. These different models should be tested through a collaboration between scientists belonging to the different paradigms. If it turns out that there are different pathogenic pathways in lupus nephritis, the emerging pathogenic mechanism(s) may be encountered with new individual causal therapy modalities. Today, therapy is still unspecific and far from interfering with the cause(s) of the disorder. This review attempts to describe what we know about processes that may cause lupus nephritis and how such basic processes may be affected if we can specifically interrupt them. Secondary inflammatory mechanisms, cytokine signatures, activation of complement, and other contributors to inflammation will not be discussed herein; rather, the events that trigger these factors will be discussed.

PMID: 27664472 [PubMed - indexed for MEDLINE]




Death Receptor 3 Promotes Chemokine-Directed Leukocyte Recruitment in Acute Resolving Inflammation and Is Essential for Pathological Development of Mesothelial Fibrosis in Chronic Disease.
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Death Receptor 3 Promotes Chemokine-Directed Leukocyte Recruitment in Acute Resolving Inflammation and Is Essential for Pathological Development of Mesothelial Fibrosis in Chronic Disease.

Am J Pathol. 2016 Nov;186(11):2813-2823

Authors: Perks WV, Singh RK, Jones GW, Twohig JP, Williams AS, Humphreys IR, Taylor PR, Jones SA, Wang EC

Abstract
Death receptor 3 (DR3; TNFRSF25) and its tumor necrosis factor-like ligand TL1A (TNFSF15) control several processes in inflammatory diseases through the expansion of effector T cells and the induction of proinflammatory cytokines from myeloid and innate lymphoid cells. Using wild-type (DR3(+/+)) and DR3-knockout (DR3(-/-)) mice, we show that the DR3/TL1A pathway triggers the release of multiple chemokines after acute peritoneal inflammation initiated by a single application of Staphylococcus epidermidis supernatant, correlating with the infiltration of multiple leukocyte subsets. In contrast, leukocyte infiltration was not DR3 dependent after viral challenge with murine cytomegalovirus. DR3 expression was recorded on connective tissue stroma, which provided DR3-dependent release of chemokine (C-C motif) ligand (CCL) 2, CCL7, CXCL1, and CXCL13. CCL3, CCL4, and CXCL10 production was also DR3 dependent, but quantitative RT-PCR showed that their derivation was not stromal. In vitro cultures identified resident macrophages as a DR3-dependent source of CCL3. Whether DR3 signaling could contribute to a related peritoneal pathology was then tested using multiple applications of S. epidermidis supernatant, the repetitive inflammatory episodes of which lead to peritoneal membrane thickening and collagen deposition. Unlike their DR3(+/+) counterparts, DR3(-/-) mice did not develop fibrosis of the mesothelial layer. Thus, this work describes both a novel function and essential requirement for the DR3/TL1A pathway in acute, resolving, and chronic inflammation in the peritoneal cavity.

PMID: 27664471 [PubMed - indexed for MEDLINE]




REV-ERBα Activates C/EBP Homologous Protein to Control Small Heterodimer Partner-Mediated Oscillation of Alcoholic Fatty Liver.
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REV-ERBα Activates C/EBP Homologous Protein to Control Small Heterodimer Partner-Mediated Oscillation of Alcoholic Fatty Liver.

Am J Pathol. 2016 Nov;186(11):2909-2920

Authors: Yang Z, Tsuchiya H, Zhang Y, Lee S, Liu C, Huang Y, Vargas GM, Wang L

Abstract
The small heterodimer partner (SHP) nuclear receptor is an important regulator of nonalcoholic fatty liver disease. However, little is known about the role of SHP in alcoholic fatty liver. In this study, we used a modified chronic ethanol-binge model to examine cyclic alterations of lipid metabolism in wild-type (WT) and Shp(-/-) mice over a 24-hour period after binge. The serum and hepatic lipid profiles, as well as the expression of lipid synthesis genes and markers of endoplasmic reticulum stress, exhibited distinct variations in WT and Shp(-/-) mice in response to ethanol diet plus ethanol binge (ED+E) and control diet plus maltose binge. ED+E induced steatosis in WT mice, which correlated with a marked up-regulation of activating transcription factor 4 protein (ATF4) but down-regulation of C/EBP homologous protein (CHOP) and sterol regulatory element-binding transcription factor 1c protein (SREBP-1c). On the contrary, the control diet plus maltose binge caused lipid accumulation in Shp(-/-) mice, which was accompanied by a sharp elevation of CHOP, SREBP-1c, and REV-ERBα proteins but a diminished ATF4. REV-ERBα activated CHOP promoter activity and gene transcription, which were inhibited by SHP. Knockdown Rev-Erbα in Shp(-/-) mice prevented steatosis induced by ED+E. Our study revealed a critical role of SHP and REV-ERBα in controlling rhythmic CHOP expression in alcoholic fatty liver.

PMID: 27664470 [PubMed - indexed for MEDLINE]




Fibrogenic Signaling Is Suppressed in Hepatic Stellate Cells through Targeting of Connective Tissue Growth Factor (CCN2) by Cellular or Exosomal MicroRNA-199a-5p.
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Fibrogenic Signaling Is Suppressed in Hepatic Stellate Cells through Targeting of Connective Tissue Growth Factor (CCN2) by Cellular or Exosomal MicroRNA-199a-5p.

Am J Pathol. 2016 Nov;186(11):2921-2933

Authors: Chen L, Chen R, Velazquez VM, Brigstock DR

Abstract
Pathways of liver fibrosis are controlled by connective tissue growth factor (CCN2). In this study, CCN2 was identified as a target of miR-199a-5p, which was principally expressed in quiescent mouse hepatic stellate cells (HSCs) and directly suppressed production of CCN2. Up-regulated CCN2 expression in fibrotic mouse livers or in activated primary mouse HSCs was associated with miR-199a-5p down-regulation. MiR-199a-5p in quiescent mouse HSCs inhibited the activity of a wild-type CCN2 3' untranslated region (3'-UTR) but not of a mutant CCN2 3'-UTR lacking the miR-199a-5p-binding site. In activated mouse HSCs, CCN2, α-smooth muscle actin, and collagen 1(α1) were suppressed by a miR-199a-5p mimic, whereas in quiescent mouse HSCs, the inhibited CCN2 3'-UTR activity was blocked by a miR-199a-5p antagomir. CCN2 3'-UTR activity in human HSCs was reduced by a miR-199a-5p mimic. MiR-199a-5p was present at higher levels in exosomes from quiescent versus activated HSCs. MiR-199a-5p-containing exosomes were shuttled from quiescent mouse HSCs to activated mouse HSCs in which CCN2 3'-UTR activity was then suppressed. Exosomes from quiescent HSCs caused miR-199a-5p-dependent inhibition of CCN2, α-smooth muscle actin, or collagen 1(α1) in activated HSCs in vitro and bound to activated HSCs in vivo. Thus, CCN2 suppression by miR-199a-5p accounts, in part, for low-level fibrogenic gene expression in quiescent HSCs and causes dampened gene expression in activated HSCs after horizontal transfer of miR-199a-5p in exosomes from quiescent HSCs.

PMID: 27662798 [PubMed - indexed for MEDLINE]




Heme Oxygenase 1 Up-Regulates Glomerular Decay Accelerating Factor Expression and Minimizes Complement Deposition and Injury.
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Heme Oxygenase 1 Up-Regulates Glomerular Decay Accelerating Factor Expression and Minimizes Complement Deposition and Injury.

Am J Pathol. 2016 Nov;186(11):2833-2845

Authors: Detsika MG, Duann P, Atsaves V, Papalois A, Lianos EA

Abstract
Complement-activation controllers, including decay accelerating factor (DAF), are gaining emphasis as they minimize injury in various dysregulated complement-activation disorders, including glomerulopathies. Heme oxygenase (HO)-1 overexpression or induction has been shown to attenuate injury in complement-dependent models of glomerulonephritis. This study investigated whether up-regulation of DAF by heme oxygenase 1 (HO-1) is an underlying mechanism by using Hmox-1-deficient rats (Hmox1(+/-); Hmox1(-/-)) or rats with HO-1 overexpression targeted to glomerular epithelial cells (GEC(HO-1)), which are particularly vulnerable to complement-mediated injury owing to their terminally differentiated nature. Constitutively expressed DAF was decreased in glomeruli of Hmox1(-/-) rats and augmented in glomeruli of GEC(HO-1) rats. In GEC(HO-1) rats with anti-glomerular basement membrane antibody mediated, complement-dependent injury, complement component C3 fragment b (C3b) deposition was reduced, whereas proteinuria was diminished. In glomeruli of wild-type rats, the natural Hmox substrate, hemin, induced glomerular DAF. This effect was attenuated in glomeruli of Hmox1(-/-) rats and augmented in glomeruli of GEC(HO-1) rats. Hemin analogues differing in either metal or porphyrin ring functionalities, acting as competitive Hmox-substrate inhibitors, also increased glomerular DAF and reduced C3b deposition after spontaneous complement activation. In the presence of a DAF-blocking antibody, the reduction in C3b deposition was reversed. These observations establish HO-1 as a physiologic regulator of glomerular DAF and identify hemin analogues as inducers of functional glomerular DAF able to minimize C3b deposition.

PMID: 27662796 [PubMed - indexed for MEDLINE]




Prolonged Repetitive Head Trauma Induces a Singular Chronic Traumatic Encephalopathy-Like Pathology in White Matter Despite Transient Behavioral Abnormalities.
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Prolonged Repetitive Head Trauma Induces a Singular Chronic Traumatic Encephalopathy-Like Pathology in White Matter Despite Transient Behavioral Abnormalities.

Am J Pathol. 2016 Nov;186(11):2869-2886

Authors: Briggs DI, Angoa-Pérez M, Kuhn DM

Abstract
Repetitive mild traumatic brain injury (rmTBI), resulting from insults caused by an external mechanical force that disrupts normal brain function, has been linked to the development of neurodegenerative diseases, such as chronic traumatic encephalopathy and Alzheimer disease; however, neither the severity nor frequency of head injury required to trigger adverse behavioral outcomes is well understood. In this study, the administration of 30 head impacts using two different weights to lightly anesthetized, completely unrestrained mice established a paradigm that simulates the highly repetitive nature of sports- and military-related head injury. As the number of head impacts increases, the time to recover consciousness diminishes; however, both the sensorimotor function and behavioral outcomes of impacted mice evolve during the ensuing weeks. Postmortem analyses reveal robust Alzheimer disease and chronic traumatic encephalopathy-like conditions that manifest in a singular manner throughout the white matter concomitant with evidence of chronic oligodendrogenesis. Our data suggest that latency to recover the righting reflex may be an inadequate measure of injury severity and imply that exposure to repeated head impacts may mask the severity of an underlying and developing neuropathologic condition that does not manifest itself until long after head collisions cease. In addition, our data indicate that there is a cumulative and dose-dependent effect of repetitive head impacts that induces the neurobehavioral and neuropathologic outcomes seen in humans with a history of rmTBI.

PMID: 27662795 [PubMed - indexed for MEDLINE]




Adipocyte-Lineage Cells Support Growth and Dissemination of Multiple Myeloma in Bone.
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Adipocyte-Lineage Cells Support Growth and Dissemination of Multiple Myeloma in Bone.

Am J Pathol. 2016 Nov;186(11):3054-3063

Authors: Trotter TN, Gibson JT, Sherpa TL, Gowda PS, Peker D, Yang Y

Abstract
Multiple myeloma (MM) cells reside in the bone marrow microenvironment and form complicated interactions with nonneoplastic, resident stromal cells. We previously found that aggressive MM cells shift osteoblast progenitors toward adipogenesis. In addition, adipocytes are among the most common cell types in the adult skeleton; both mature adipocytes and preadipocytes serve as endocrine cells that secrete a number of soluble molecules into the microenvironment. Therefore, we used a combination of in vivo and in vitro methods to test the hypothesis that an increase in adipocyte lineage cells feeds back to promote MM progression. The results of this study revealed that bone marrow from patients with MM indeed contains increased preadipocytes and significantly larger mature adipocytes than normal bone marrow. We also found that preadipocytes and mature adipocytes secrete many molecules important for supporting MM cells in the bone marrow and directly recruit MM cells through both monocyte chemotactic protein-1 and stromal cell-derived factor-1α. Co-culture experiments found that preadipocytes activate Wnt signaling and decrease cleaved caspase-3, whereas mature adipocytes activate ERK signaling in MM cells. Furthermore, mature adipocyte conditioned medium promotes MM growth, whereas co-culture with preadipocytes results in enhanced MM cell chemotaxis in vitro and increased tumor growth in bone in vivo. Combined, these data reveal the importance of preadipocytes and mature adipocytes on MM progression and represent a unique target in the bone marrow microenvironment.

PMID: 27648615 [PubMed - indexed for MEDLINE]




Necrotic Bone Stimulates Proinflammatory Responses in Macrophages through the Activation of Toll-Like Receptor 4.
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Necrotic Bone Stimulates Proinflammatory Responses in Macrophages through the Activation of Toll-Like Receptor 4.

Am J Pathol. 2016 Nov;186(11):2987-2999

Authors: Adapala NS, Yamaguchi R, Phipps M, Aruwajoye O, Kim HK

Abstract
In Legg-Calvé-Perthes disease, loss of blood supply results in ischemic osteonecrosis of the femoral head (ONFH). Generally, macrophages play important roles in inflammatory responses to tissue necrosis, but their role in ONFH is not known. The purpose of this study was to determine the macrophage-inflammatory responses after ONFH and the receptor mechanisms involved in sensing the necrotic bone, using a piglet model of Legg-Calvé-Perthes disease. Induction of ONFH resulted in increased numbers of CD14(+) macrophages in the fibrovascular repair tissue compared with normal, as determined by immunohistochemistry. Quantitative real-time PCR analysis of macrophages isolated by laser capture microdissection showed significantly increased expression of proinflammatory cytokines IL-1β, tumor necrosis factor-α, and IL-6 in ONFH compared with normal. Because Toll-like receptors (TLRs) mediate macrophage-inflammatory responses in other inflammatory conditions, we determined their gene expression in macrophages and found significantly increased levels of TLR4 but not TLR2 and TLR9 in ONFH. Mechanistically, in vitro, bone marrow-derived macrophages treated with necrotic bone showed increased extracellular signal-regulated kinases 1/2 and Iκ kinase-α phosphorylation, increased proliferation, migration, and inflammatory cytokine expression, which were blocked by TLR4 inhibitor, TAK242, and by TLR4 ablation in macrophages using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease method. In conclusion, necrotic bone stimulates macrophage-inflammatory responses through TLR4 activation.

PMID: 27648614 [PubMed - indexed for MEDLINE]




Accumulation of Ubiquitin and Sequestosome-1 Implicate Protein Damage in Diacetyl-Induced Cytotoxicity.
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Accumulation of Ubiquitin and Sequestosome-1 Implicate Protein Damage in Diacetyl-Induced Cytotoxicity.

Am J Pathol. 2016 Nov;186(11):2887-2908

Authors: Hubbs AF, Fluharty KL, Edwards RJ, Barnabei JL, Grantham JT, Palmer SM, Kelly F, Sargent LM, Reynolds SH, Mercer RR, Goravanahally MP, Kashon ML, Honaker JC, Jackson MC, Cumpston AM, Goldsmith WT, McKinney W, Fedan JS, Battelli LA, Munro T, Bucklew-Moyers W, McKinstry K, Schwegler-Berry D, Friend S, Knepp AK, Smith SL, Sriram K

Abstract
Inhaled diacetyl vapors are associated with flavorings-related lung disease, a potentially fatal airway disease. The reactive α-dicarbonyl group in diacetyl causes protein damage in vitro. Dicarbonyl/l-xylulose reductase (DCXR) metabolizes diacetyl into acetoin, which lacks this α-dicarbonyl group. To investigate the hypothesis that flavorings-related lung disease is caused by in vivo protein damage, we correlated diacetyl-induced airway damage in mice with immunofluorescence for markers of protein turnover and autophagy. Western immunoblots identified shifts in ubiquitin pools. Diacetyl inhalation caused dose-dependent increases in bronchial epithelial cells with puncta of both total ubiquitin and K63-ubiquitin, central mediators of protein turnover. This response was greater in Dcxr-knockout mice than in wild-type controls inhaling 200 ppm diacetyl, further implicating the α-dicarbonyl group in protein damage. Western immunoblots demonstrated decreased free ubiquitin in airway-enriched fractions. Transmission electron microscopy and colocalization of ubiquitin-positive puncta with lysosomal-associated membrane proteins 1 and 2 and with the multifunctional scaffolding protein sequestosome-1 (SQSTM1/p62) confirmed autophagy. Surprisingly, immunoreactive SQSTM1 also accumulated in the olfactory bulb of the brain. Olfactory bulb SQSTM1 often congregated in activated microglial cells that also contained olfactory marker protein, indicating neuronophagia within the olfactory bulb. This suggests the possibility that SQSTM1 or damaged proteins may be transported from the nose to the brain. Together, these findings strongly implicate widespread protein damage in the etiology of flavorings-related lung disease.

PMID: 27643531 [PubMed - indexed for MEDLINE]




Electrical Stimulation as a Means for Improving Vision.
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Electrical Stimulation as a Means for Improving Vision.

Am J Pathol. 2016 Nov;186(11):2783-2797

Authors: Sehic A, Guo S, Cho KS, Corraya RM, Chen DF, Utheim TP

Abstract
Evolving research has provided evidence that noninvasive electrical stimulation (ES) of the eye may be a promising therapy for either preserving or restoring vision in several retinal and optic nerve diseases. In this review, we focus on minimally invasive strategies for the delivery of ES and accordingly summarize the current literature on transcorneal, transorbital, and transpalpebral ES in both animal experiments and clinical studies. Various mechanisms are believed to underlie the effects of ES, including increased production of neurotrophic agents, improved chorioretinal blood circulation, and inhibition of proinflammatory cytokines. Different animal models have demonstrated favorable effects of ES on both the retina and the optic nerve. Promising effects of ES have also been demonstrated in clinical studies; however, all current studies have a lack of randomization and/or a control group (sham). There is thus a pressing need for a deeper understanding of the underlying mechanisms that govern clinical success and optimization of stimulation parameters in animal studies. In addition, such research should be followed by large, prospective, clinical studies to explore the full potential of ES. Through this review, we aim to provide insight to guide future research on ES as a potential therapy for improving vision.

PMID: 27643530 [PubMed - indexed for MEDLINE]




C-C Motif Chemokine 5 Attenuates Angiotensin II-Dependent Kidney Injury by Limiting Renal Macrophage Infiltration.
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C-C Motif Chemokine 5 Attenuates Angiotensin II-Dependent Kidney Injury by Limiting Renal Macrophage Infiltration.

Am J Pathol. 2016 Nov;186(11):2846-2856

Authors: Rudemiller NP, Patel MB, Zhang JD, Jeffs AD, Karlovich NS, Griffiths R, Kan MJ, Buckley AF, Gunn MD, Crowley SD

Abstract
Inappropriate activation of the renin angiotensin system (RAS) is a key contributor to the pathogenesis of essential hypertension. During RAS activation, infiltration of immune cells into the kidney exacerbates hypertension and renal injury. However, the mechanisms underpinning the accumulation of mononuclear cells in the kidney after RAS stimulation remain unclear. C-C motif chemokine 5 (CCL5) drives recruitment of macrophages and T lymphocytes into injured tissues, and we have found that RAS activation induces CCL5 expression in the kidney during the pathogenesis of hypertension and renal fibrosis. We therefore evaluated the contribution of CCL5 to renal damage and fibrosis in hypertensive and normotensive models of RAS stimulation. Surprisingly, during angiotensin II-induced hypertension, CCL5-deficient (knockout, KO) mice exhibited markedly augmented kidney damage, macrophage infiltration, and expression of proinflammatory macrophage cytokines compared with wild-type controls. When subjected to the normotensive unilateral ureteral obstruction model of endogenous RAS activation, CCL5 KO mice similarly developed more severe renal fibrosis and greater accumulation of macrophages in the kidney, congruent with enhanced renal expression of the macrophage chemokine CCL2. In turn, pharmacologic inhibition of CCL2 abrogated the differences between CCL5 KO and wild-type mice in kidney fibrosis and macrophage infiltration after unilateral ureteral obstruction. These data indicate that CCL5 paradoxically limits macrophage accumulation in the injured kidney during RAS activation by constraining the proinflammatory actions of CCL2.

PMID: 27640148 [PubMed - indexed for MEDLINE]




Discoidin Domain Receptor 2 as a Potential Therapeutic Target for Development of Disease-Modifying Osteoarthritis Drugs.
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Discoidin Domain Receptor 2 as a Potential Therapeutic Target for Development of Disease-Modifying Osteoarthritis Drugs.

Am J Pathol. 2016 Nov;186(11):3000-3010

Authors: Manning LB, Li Y, Chickmagalur NS, Li X, Xu L

Abstract
Osteoarthritis (OA) is the most common form of arthritis disorders, but the identification of therapeutic targets to effectively prevent OA has been increasingly difficult. The goal of this investigation is to provide experimental evidence that discoidin domain receptor 2 (DDR2) may be an ideal target for the development of disease-modifying OA drugs. Ddr2 was conditionally deleted from articular cartilage of adult mouse knee joints. Aggrecan-CreERT2;floxed Ddr2 mice, which were generated by crossing Aggrecan-CreERT2 mice with floxed Ddr2 mice, then received tamoxifen injections at the age of 8 weeks. The mice were then subjected to destabilization of the medial meniscus (DMM) surgery. At 8 and 16 weeks after DMM, mice were euthanized for the collection of knee joints. In a separate experiment, Aggrecan-CreERT2;floxed Ddr2 mice were subjected to DMM at the age of 10 weeks. The mice then received tamoxifen injections at 8 weeks after DMM. The mice were euthanized for the collection of knee joints at 16 weeks after DMM. The progressive process of articular cartilage degeneration was significantly delayed in the knee joints of Ddr2-deficient mice in comparison to their control littermates. Articular cartilage damage in the knee joints of the mice was associated with increased expression profiles of both Ddr2 and matrix metalloproteinase 13. These findings suggest that DDR2 may be an ideal target for the development of disease-modifying OA drugs.

PMID: 27640147 [PubMed - indexed for MEDLINE]




Endothelin-1 Treatment Induces an Experimental Cerebral Malaria-Like Syndrome in C57BL/6 Mice Infected with Plasmodium berghei NK65.
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Endothelin-1 Treatment Induces an Experimental Cerebral Malaria-Like Syndrome in C57BL/6 Mice Infected with Plasmodium berghei NK65.

Am J Pathol. 2016 Nov;186(11):2957-2969

Authors: Martins YC, Freeman BD, Akide Ndunge OB, Weiss LM, Tanowitz HB, Desruisseaux MS

Abstract
Plasmodium berghei ANKA infection of C57BL/6 mice is a widely used model of experimental cerebral malaria (ECM). By contrast, the nonneurotropic P. berghei NK65 (PbN) causes severe malarial disease in C57BL/6 mice but does not cause ECM. Previous studies suggest that endothelin-1 (ET-1) contributes to the pathogenesis of ECM. In this study, we characterize the role of ET-1 on ECM vascular dysfunction. Mice infected with 10(6) PbN-parasitized red blood cells were treated with either ET-1 or saline from 2 to 8 days postinfection (dpi). Plasmodium berghei ANKA-infected mice served as the positive control. ET-1-treated PbN-infected mice exhibited neurological signs, hypothermia, and behavioral alterations characteristic of ECM, dying 4 to 8 dpi. Parasitemia was not affected by ET-1 treatment. Saline-treated PbN-infected mice did not display ECM, surviving until 12 dpi. ET-1-treated PbN-infected mice displayed leukocyte adhesion to the vascular endothelia and petechial hemorrhages throughout the brain at 6 dpi. Intravital microscopic images demonstrated significant brain arteriolar vessel constriction, decreased functional capillary density, and increased blood-brain barrier permeability. These alterations were not present in either ET-1-treated uninfected or saline-treated PbN-infected mice. In summary, ET-1 treatment of PbN-infected mice induced an ECM-like syndrome, causing brain vasoconstriction, adherence of activated leukocytes in the cerebral microvasculature, and blood-brain barrier leakage, indicating that ET-1 is involved in the genesis of brain microvascular alterations that are the hallmark of ECM.

PMID: 27640146 [PubMed - indexed for MEDLINE]




Dynamin-Related Protein 1 Deficiency Leads to Receptor-Interacting Protein Kinase 3-Mediated Necroptotic Neurodegeneration.
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Dynamin-Related Protein 1 Deficiency Leads to Receptor-Interacting Protein Kinase 3-Mediated Necroptotic Neurodegeneration.

Am J Pathol. 2016 Nov;186(11):2798-2802

Authors: Yamada T, Adachi Y, Fukaya M, Iijima M, Sesaki H

Abstract
Mitochondria are dynamic organelles that divide and fuse to modulate their number and shape. We have previously reported that the loss of dynamin-related protein 1 (Drp1), which mediates mitochondrial division, leads to the degeneration of cerebellar Purkinje cells in mice. Because Drp1 has been shown to be important for apoptosis and necroptosis, it is puzzling how Purkinje neurons die in the absence of Drp1. In this study, we tested whether neurodegeneration involves necrotic cell death by generating Purkinje cell-specific Drp1-knockout (KO) mice that lack the receptor-interacting protein kinase 3 (Rip3), which regulates necroptosis. We found that the loss of Rip3 significantly delays the degeneration of Drp1-KO Purkinje neurons. In addition, before neurodegeneration, mitochondrial tubules elongate because of unopposed fusion and subsequently become large spheres as a result of oxidative damage. Surprisingly, Rip3 loss also helps Drp1-KO Purkinje cells maintain the elongated morphology of the mitochondrial tubules. These data suggest that Rip3 plays a role in neurodegeneration and mitochondrial morphology in the absence of mitochondrial division.

PMID: 27640145 [PubMed - indexed for MEDLINE]




Hes1 Controls Exocrine Cell Plasticity and Restricts Development of Pancreatic Ductal Adenocarcinoma in a Mouse Model.
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Hes1 Controls Exocrine Cell Plasticity and Restricts Development of Pancreatic Ductal Adenocarcinoma in a Mouse Model.

Am J Pathol. 2016 Nov;186(11):2934-2944

Authors: Hidalgo-Sastre A, Brodylo RL, Lubeseder-Martellato C, Sipos B, Steiger K, Lee M, von Figura G, Grünwald B, Zhong S, Trajkovic-Arsic M, Neff F, Schmid RM, Siveke JT

Abstract
Perturbation of pancreatic acinar cell state can lead to acinar-to-ductal metaplasia (ADM), a precursor lesion to the development of pancreatic ductal adenocarcinoma (PDAC). In the pancreas, Notch signaling is active both during development and in adult cellular differentiation processes. Hes1, a key downstream target of the Notch signaling pathway, is expressed in the centroacinar compartment of the adult pancreas as well as in both preneoplastic and malignant lesions. In this study, we used a murine genetic in vivo approach to ablate Hes1 in pancreatic progenitor cells (Ptf1a(+/Cre); Hes1(fl/fl)). Using this model, we studied the role of Hes1 in both acinar cell plasticity and pancreatic regeneration after caerulein-induced pancreatitis and in Kras(G12D)-driven PDAC development. We show that, although pancreatic development is not perturbed on the deletion of Hes1, terminal acinar differentiation in the adult pancreas is compromised. Moreover, the loss of Hes1 leads to the impaired regeneration of the exocrine compartment, accelerated fatty metaplasia, and persistent ADM after acute caerulein-induced pancreatitis. In Kras(G12D)-driven carcinogenesis, Hes1 ablation resulted in increased ADM, decreased formation of high-grade pancreatic intraepithelial neoplasias, and accelerated development of PDAC with shortened survival time. In conclusion, Hes1 plays a key role in acinar cell integrity and plasticity on cellular insults. Furthermore, Hes1 is an essential component of the pancreatic intraepithelial neoplasias-to-PDAC route in Kras(G12D)-driven mouse pancreatic carcinogenesis.

PMID: 27639167 [PubMed - indexed for MEDLINE]




Formaldehyde Is a Potent Proteotoxic Stressor Causing Rapid Heat Shock Transcription Factor 1 Activation and Lys48-Linked Polyubiquitination of Proteins.
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Formaldehyde Is a Potent Proteotoxic Stressor Causing Rapid Heat Shock Transcription Factor 1 Activation and Lys48-Linked Polyubiquitination of Proteins.

Am J Pathol. 2016 Nov;186(11):2857-2868

Authors: Ortega-Atienza S, Rubis B, McCarthy C, Zhitkovich A

Abstract
Endogenous and exogenous formaldehyde (FA) has been linked to cancer, neurotoxicity, and other pathophysiologic effects. Molecular and cellular mechanisms that underlie FA-induced damage are poorly understood. In this study, we investigated whether proteotoxicity is an important, unrecognized factor in cell injury caused by FA. We found that irrespective of their cell cycle phases, all FA-treated human cells rapidly accumulated large amounts of proteins with proteasome-targeting K48-linked polyubiquitin, which was comparable with levels of polyubiquitination in proteasome-inhibited MG132 controls. Both nuclear and cytoplasmic proteins were damaged and underwent K48-polyubiquitination. There were no significant changes in the nonproteolytic K63-polyubiquitination of soluble and insoluble cellular proteins. FA also rapidly induced nuclear accumulation and Ser326 phosphorylation of the main heat shock-responsive transcription factor HSF1, which was not a result of protein polyubiquitination. Consistent with the activation of the functional heat shock response, FA strongly elevated the expression of HSP70 genes. In contrast to the responsiveness of the cytoplasmic protein damage sensor HSF1, FA did not activate the unfolded protein response in either the endoplasmic reticulum or mitochondria. Inhibition of HSP90 chaperone activity increased the levels of K48-polyubiquitinated proteins and diminished cell viability after FA treatment. Overall, our results indicate that FA is a strong proteotoxic agent, which helps explain its diverse pathologic effects, including injury in nonproliferative tissues.

PMID: 27639166 [PubMed - indexed for MEDLINE]




Role of Integrins α1β1 and α2β1 in Wound and Tumor Angiogenesis in Mice.
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Role of Integrins α1β1 and α2β1 in Wound and Tumor Angiogenesis in Mice.

Am J Pathol. 2016 Nov;186(11):3011-3027

Authors: Ghatak S, Niland S, Schulz JN, Wang F, Eble JA, Leitges M, Mauch C, Krieg T, Zigrino P, Eckes B

Abstract
Integrins are transmembrane receptors composed of one α subunit and one β subunit and are involved in cellular growth, differentiation, and apoptosis. The collagen-binding integrins α1β1 and α2β1 have been shown to regulate wound and tumor vascularization by different mechanisms. In this study, we assessed wound and tumor vascularization in mice with genetic ablation of both integrin subunits α1 and α2, which resulted in loss of integrins α1β1 and α2β1. Wound angiogenesis was investigated in excisional wounds that were inflicted on the back skin of control and mice lacking integrin α1β1 and α2β1. Mutant mice displayed reduced wound angiogenesis, which correlated with decreased macrophage numbers at 3 and 7 days after injury, and showed significantly attenuated vascularization of sponge implants. Angiogenesis induced by tumors arising from intradermal injection of B16 F1 melanoma cells was also reduced in comparison to controls 7 days after injection. This reduction in angiogenesis correlated with increased levels and activity of circulating matrix metalloproteinase 9 and elevated angiostatin levels in plasma of mutant mice, which reduced endothelial cell proliferation. Ex vivo mutant aortic ring explants developed significantly fewer and thinner aortic sprouts with fewer branch points than controls because of impaired endothelial cell proliferation. In conclusion, the loss of integrins α1β1 and α2β1 in mice results in reduced wound and tumor angiogenesis by cell-autonomous and extrinsic mechanisms.

PMID: 27639165 [PubMed - indexed for MEDLINE]




Cellular Prion Protein Mediates Pancreatic Cancer Cell Survival and Invasion through Association with and Enhanced Signaling of Notch1.
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Cellular Prion Protein Mediates Pancreatic Cancer Cell Survival and Invasion through Association with and Enhanced Signaling of Notch1.

Am J Pathol. 2016 Nov;186(11):2945-2956

Authors: Wang Y, Yu S, Huang D, Cui M, Hu H, Zhang L, Wang W, Parameswaran N, Jackson M, Osborne B, Bedogni B, Li C, Sy MS, Xin W, Zhou L

Abstract
Up-regulation of human prion protein (PrP) in patients with pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis. However, the underlying molecular mechanism of PrP-mediated tumorigenesis is not completely understood. In this study, we found that PDAC cell lines can be divided into either PrP high expresser or PrP low expresser. In addition to filamin A (FLNA), PrP interacts with Notch1, forming a PrP/FLNA/Notch1 complex. Silencing PrP in high-expresser cells decreases Notch1 expression and Notch1 signaling. These cells exhibited decreased proliferation, xenograft growth, and tumor invasion but show increased tumor apoptosis. These phenotypes were rescued by ectopically expressed and activated Notch1. By contrast, overexpression of PrP in low expressers increases Notch1 expression and signaling, enhances proliferation, and increases tumor invasion and xenograft growth that can be blocked by a Notch inhibitor. Our data further suggest that PrP increases Notch1 stability likely through suppression of Notch proteosome degradation. Additionally, we found that targeting PrP combined with anti-Notch is much more effective than singularly targeted therapy in retarding PDAC growth. Finally, we show that coexpression of PrP and Notch1 confers an even poorer prognosis than PrP expression alone. Taken together, our results have unraveled a novel molecular pathway driven by interactions between PrP and Notch1 in the progression of PDAC, supporting a critical tumor-promoting role of Notch1 in PrP-expressing PDAC tumors.

PMID: 27639164 [PubMed - indexed for MEDLINE]




Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta.
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Persistent Cytomegalovirus Infection in Amniotic Membranes of the Human Placenta.

Am J Pathol. 2016 Nov;186(11):2970-2986

Authors: Tabata T, Petitt M, Fang-Hoover J, Zydek M, Pereira L

Abstract
Human cytomegalovirus (HCMV) is the leading viral cause of birth defects, including microcephaly, neurological deficits, hearing impairment, and vision loss. We previously reported that epithelial cells in amniotic membranes of placentas from newborns with intrauterine growth restriction and underlying congenital HCMV infection contain viral proteins in cytoplasmic vesicles. Herein, we immunostained amniotic membranes from 51 placentas from symptomatic and asymptomatic congenital infection with HCMV DNA in amniotic fluid and/or newborn saliva, intrauterine growth restriction, preterm deliveries, and controls. We consistently observed HCMV proteins in amniotic epithelial cells (AmEpCs) from infected placentas, sometimes with aberrant morphology. Primary AmEpCs isolated from mid-gestation placentas infected with pathogenic VR1814 proliferated and released infectious progeny for weeks, producing higher virus titers than late-gestation cells that varied by donor. In contrast to intact virion assembly compartments in differentiated retinal pigment epithelial cells, infected AmEpCs made dispersed multivesicular bodies. Primary AmEpCs and explants of amniochorionic membranes from mid-gestation placentas formed foci of infection, and interferon-β production was prolonged. Infected AmEpCs up-regulated anti-apoptotic proteins survivin and Bcl-xL by mechanisms dependent and independent of the activated STAT3. Amniotic membranes naturally expressed both survivin and Bcl-xL, indicating that fetal membranes could foster persistent viral infection. Our results suggest strengthening innate immune responses and reducing viral functions could suppress HCMV infection in the fetal compartment.

PMID: 27638253 [PubMed - indexed for MEDLINE]