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https://www.readbyqxmd.com/read/28724806/nicotinamide-mononucleotide-requires-sirt3-to-improve-cardiac-function-and-bioenergetics-in-a-friedreich-s-ataxia-cardiomyopathy-model
#1
Angelical S Martin, Dennis M Abraham, Kathleen A Hershberger, Dhaval P Bhatt, Lan Mao, Huaxia Cui, Juan Liu, Xiaojing Liu, Michael J Muehlbauer, Paul A Grimsrud, Jason W Locasale, R Mark Payne, Matthew D Hirschey
Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. While NMN influences several aspects of mitochondrial metabolism, the molecular mechanisms by which increased NAD+ enhances cardiac function are poorly understood. A putative mechanism of NAD+ therapeutic action exists via activation of the mitochondrial NAD+-dependent protein deacetylase sirtuin 3 (SIRT3). We assessed the therapeutic efficacy of NMN and the role of SIRT3 in the Friedreich's ataxia cardiomyopathy mouse model (FXN-KO)...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724805/diabetic-retinopathy-current-understanding-mechanisms-and-treatment-strategies
#2
REVIEW
Elia J Duh, Jennifer K Sun, Alan W Stitt
Diabetic retinopathy (DR) causes significant visual loss on a global scale. Treatments for the vision-threatening complications of diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) have greatly improved over the past decade. However, additional therapeutic options are needed that take into account pathology associated with vascular, glial, and neuronal components of the diabetic retina. Recent work indicates that diabetes markedly impacts the retinal neurovascular unit and its interdependent vascular, neuronal, glial, and immune cells...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724804/pediatric-dilated-cardiomyopathy-hearts-display-a-unique-gene-expression-profile
#3
Philip D Tatman, Kathleen C Woulfe, Anis Karimpour-Fard, Danielle A Jeffrey, James Jaggers, Joseph C Cleveland, Karin Nunley, Matthew Rg Taylor, Shelley D Miyamoto, Brian L Stauffer, Carmen C Sucharov
Our previous work showed myocellular differences in pediatric and adult dilated cardiomyopathy (DCM). However, a thorough characterization of the molecular pathways involved in pediatric DCM does not exist, limiting the development of age-specific therapies. To characterize this patient population, we investigated the transcriptome profile of pediatric patients. RNA-Seq from 7 DCM and 7 nonfailing (NF) explanted age-matched pediatric left ventricles (LV) was performed. Changes in gene expression were confirmed by real-time PCR (RT-PCR) in 36 DCM and 21 NF pediatric hearts and in 20 DCM and 10 NF adult hearts...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724803/increased-de-novo-ceramide-synthesis-and-accumulation-in-failing-myocardium
#4
Ruiping Ji, Hirokazu Akashi, Konstantinos Drosatos, Xianghai Liao, Hongfeng Jiang, Peter J Kennel, Danielle L Brunjes, Estibaliz Castillero, Xiaokan Zhang, Lily Y Deng, Shunichi Homma, Isaac J George, Hiroo Takayama, Yoshifumi Naka, Ira J Goldberg, P Christian Schulze
No abstract text is available yet for this article.
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724802/partially-exhausted-tumor-infiltrating-lymphocytes-predict-response-to-combination-immunotherapy
#5
Kimberly Loo, Katy K Tsai, Kelly Mahuron, Jacqueline Liu, Mariela L Pauli, Priscila M Sandoval, Adi Nosrati, James Lee, Lawrence Chen, Jimmy Hwang, Lauren S Levine, Matthew F Krummel, Alain P Algazi, Michael D Alvarado, Michael D Rosenblum, Adil I Daud
BACKGROUND: Programmed death 1 (PD-1) inhibition activates partially exhausted cytotoxic T lymphocytes (peCTLs) and induces tumor regression. We previously showed that the peCTL fraction predicts response to anti-PD-1 monotherapy. Here, we sought to correlate peCTL and regulatory T lymphocyte (Treg) levels with response to combination immunotherapy, and with demographic/disease characteristics, in metastatic melanoma patients. METHODS: Pretreatment melanoma samples underwent multiparameter flow cytometric analysis...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724801/tcr-ligand-dissociation-rate-is-a-robust-and-stable-biomarker-of-cd8-t-cell-potency
#6
Mathilde Allard, Barbara Couturaud, Laura Carretero-Iglesia, Minh Ngoc Duong, Julien Schmidt, Gwennaëlle C Monnot, Pedro Romero, Daniel E Speiser, Michael Hebeisen, Nathalie Rufer
Despite influencing many aspects of T cell biology, the kinetics of T cell receptor (TCR) binding to peptide-major histocompatibility molecules (pMHC) remain infrequently determined in patient monitoring or for adoptive T cell therapy. Using specifically designed reversible fluorescent pMHC multimeric complexes, we performed a comprehensive study of TCR-pMHC off-rates combined with various functional assays on large libraries of self/tumor- and virus-specific CD8+ T cell clones from melanoma patients and healthy donors...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724800/siglec-g-represses-damp-mediated-effects-on-t-cells
#7
Tomomi Toubai, Corinne Rossi, Katherine Oravecz-Wilson, Cynthia Zajac, Chen Liu, Thomas Braun, Hideaki Fujiwara, Julia Wu, Yaping Sun, Stuart Brabbs, Hiroya Tamaki, John Magenau, Pang Zheng, Yang Liu, Pavan Reddy
The role of negative regulators or suppressors of the damage-associated molecular pattern-mediated (DAMP-mediated) stimulation of innate immune responses is being increasingly appreciated. However, the presence and function of suppressors of DAMP-mediated effects on T cells, and whether they can be targeted to mitigate T cell-dependent immunopathology remain unknown. Sialic acid-binding immunoglobulin-like lectin G (Siglec-G) is a negative regulator of DAMP-mediated responses in innate immune cells, but its T cell-autonomous role is unknown...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724799/galantamine-alleviates-inflammation-and-insulin-resistance-in-patients-with-metabolic-syndrome-in-a-randomized-trial
#8
Fernanda M Consolim-Colombo, Carine T Sangaleti, Fernando O Costa, Tercio L Morais, Heno F Lopes, Josiane M Motta, Maria C Irigoyen, Luiz A Bortoloto, Carlos Eduardo Rochitte, Yael Tobi Harris, Sanjaya K Satapathy, Peder S Olofsson, Meredith Akerman, Sangeeta S Chavan, Meggan MacKay, Douglas P Barnaby, Martin L Lesser, Jesse Roth, Kevin J Tracey, Valentin A Pavlov
BACKGROUND: Metabolic syndrome (MetS) is an obesity-driven condition of pandemic proportions that increases the risk of type 2 diabetes and cardiovascular disease. Pathophysiological mechanisms are poorly understood, though inflammation has been implicated in MetS pathogenesis. The aim of this study was to assess the effects of galantamine, a centrally acting acetylcholinesterase inhibitor with antiinflammatory properties, on markers of inflammation implicated in insulin resistance and cardiovascular risk, and other metabolic and cardiovascular indices in subjects with MetS...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724798/hepatic-jak2-protects-against-atherosclerosis-through-circulating-igf-1
#9
Tharini Sivasubramaniyam, Stephanie A Schroer, Angela Li, Cynthia T Luk, Sally Yu Shi, Rickvinder Besla, David W Dodington, Adam H Metherel, Alex P Kitson, Jara J Brunt, Joshua Lopes, Kay-Uwe Wagner, Richard P Bazinet, Michelle P Bendeck, Clinton S Robbins, Minna Woo
Atherosclerosis is considered both a metabolic and inflammatory disease; however, the specific tissue and signaling molecules that instigate and propagate this disease remain unclear. The liver is a central site of inflammation and lipid metabolism that is critical for atherosclerosis, and JAK2 is a key mediator of inflammation and, more recently, of hepatic lipid metabolism. However, precise effects of hepatic Jak2 on atherosclerosis remain unknown. We show here that hepatic Jak2 deficiency in atherosclerosis-prone mouse models exhibited accelerated atherosclerosis with increased plaque macrophages and decreased plaque smooth muscle cell content...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724797/increasing-the-level-of-peroxisome-proliferator-activated-receptor-%C3%AE-coactivator-1%C3%AE-in-podocytes-results-in-collapsing-glomerulopathy
#10
Szu-Yuan Li, Jihwan Park, Chengxiang Qiu, Seung Hyeok Han, Matthew B Palmer, Zoltan Arany, Katalin Susztak
Inherited and acquired mitochondrial defects have been associated with podocyte dysfunction and chronic kidney disease (CKD). Peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α) is one of the main transcriptional regulators of mitochondrial biogenesis and function. We hypothesized that increasing PGC1α expression in podocytes could protect from CKD. We found that PGC1α and mitochondrial transcript levels are lower in podocytes of patients and mouse models with diabetic kidney disease (DKD)...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724796/host-interleukin-6-production-regulates-inflammation-but-not-tryptophan-metabolism-in-the-brain-during-murine-gvhd
#11
Ludovic Belle, Vivian Zhou, Kara L Stuhr, Margaret Beatka, Emily M Siebers, Jennifer M Knight, Michael W Lawlor, Casey Weaver, Misato Hashizume, Cecilia J Hillard, William R Drobyski
Graft-versus-host disease (GVHD) induces pathological damage in peripheral target organs leading to well-characterized, organ-specific clinical manifestations. Patients with GVHD, however, can also have behavioral alterations that affect overall cognitive function, but the extent to which GVHD alters inflammatory and biochemical pathways in the brain remain poorly understood. In the current study, we employed complementary murine GVHD models to demonstrate that alloreactive donor T cells accumulate in the brain and affect a proinflammatory cytokine milieu that is associated with specific behavioral abnormalities...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724795/alx-receptor-ligands-define-a-biochemical-endotype-for-severe-asthma
#12
Isabell Ricklefs, Ioanna Barkas, Melody G Duvall, Manuela Cernadas, Nicole L Grossman, Elliot Israel, Eugene R Bleecker, Mario Castro, Serpil C Erzurum, John V Fahy, Benjamin M Gaston, Loren C Denlinger, David T Mauger, Sally E Wenzel, Suzy A Comhair, Andrea M Coverstone, Merritt L Fajt, Annette T Hastie, Mats W Johansson, Michael C Peters, Brenda R Phillips, Bruce D Levy
BACKGROUND: In health, inflammation resolution is an active process governed by specialized proresolving mediators and receptors. ALX/FPR2 receptors (ALX) are targeted by both proresolving and proinflammatory ligands for opposing signaling events, suggesting pivotal roles for ALX in the fate of inflammatory responses. Here, we determined if ALX expression and ligands were linked to severe asthma (SA). METHODS: ALX expression and levels of proresolving ligands (lipoxin A4 [LXA4], 15-epi-LXA4, and annexin A1 [ANXA1]), and a proinflammatory ligand (serum amyloid A [SAA]) were measured in bronchoscopy samples collected in Severe Asthma Research Program-3 (SA [n = 69], non-SA [NSA, n = 51] or healthy donors [HDs, n = 47])...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724794/apol1-variants-change-c-terminal-conformational-dynamics-and-binding-to-snare-protein-vamp8
#13
Sethu M Madhavan, John F O'Toole, Martha Konieczkowski, Laura Barisoni, David B Thomas, Santhi Ganesan, Leslie A Bruggeman, Matthias Buck, John R Sedor
APOL1 variants in African populations mediate resistance to trypanosomal infection but increase risk for kidney diseases through unknown mechanisms. APOL1 is expressed in glomerular podocytes and does not vary with underlying kidney disease diagnoses or APOL1 genotypes, suggesting that the kidney disease-associated variants dysregulate its function rather than its localization or abundance. Structural homology searches identified vesicle-associated membrane protein 8 (VAMP8) as an APOL1 protein interactor. VAMP8 colocalizes with APOL1 in the podocyte, and the APOL1:VAMP8 interaction was confirmed biochemically and with surface plasmon resonance...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724793/a-bag3-chaperone-complex-maintains-cardiomyocyte-function-during-proteotoxic-stress
#14
Luke M Judge, Juan A Perez-Bermejo, Annie Truong, Alexandre Js Ribeiro, Jennie C Yoo, Christina L Jensen, Mohammad A Mandegar, Nathaniel Huebsch, Robyn M Kaake, Po-Lin So, Deepak Srivastava, Beth L Pruitt, Nevan J Krogan, Bruce R Conklin
Molecular chaperones regulate quality control in the human proteome, pathways that have been implicated in many diseases, including heart failure. Mutations in the BAG3 gene, which encodes a co-chaperone protein, have been associated with heart failure due to both inherited and sporadic dilated cardiomyopathy. Familial BAG3 mutations are autosomal dominant and frequently cause truncation of the coding sequence, suggesting a heterozygous loss-of-function mechanism. However, heterozygous knockout of the murine BAG3 gene did not cause a detectable phenotype...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724792/pediatric-and-adult-dilated-cardiomyopathy-represent-distinct-pathological-entities
#15
Meghna D Patel, Jayaram Mohan, Caralin Schneider, Geetika Bajpai, Enkhsaikhan Purevjav, Charles E Canter, Jeffrey Towbin, Andrea Bredemeyer, Kory J Lavine
Pediatric dilated cardiomyopathy (DCM) is the most common indication for heart transplantation in children. Despite similar genetic etiologies, medications routinely used in adult heart failure patients do not improve outcomes in the pediatric population. The mechanistic basis for these observations is unknown. We hypothesized that pediatric and adult DCM comprise distinct pathological entities, in that children do not undergo adverse remodeling, the target of adult heart failure therapies. To test this hypothesis, we examined LV specimens obtained from pediatric and adult donor controls and DCM patients...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724791/mitochondrial-dna-enriched-microparticles-promote-acute-on-chronic-alcoholic-neutrophilia-and-hepatotoxicity
#16
Yan Cai, Ming-Jiang Xu, Erik H Koritzinsky, Zhou Zhou, Wei Wang, Haixia Cao, Peter St Yuen, Ruth A Ross, Robert A Star, Suthat Liangpunsakul, Bin Gao
Over the last several years, one of the major advances in the field of alcoholic liver disease research was the discovery that binge alcohol consumption induced neutrophilia and hepatic neutrophil infiltration in chronically ethanol-fed mice and human subjects with excessive alcohol use (EAU); however, the underlying mechanisms remain obscure. Here, we demonstrated that chronic EAU patients with a history of recent excessive drinking (EAU + RD) had higher serum levels of mitochondrial DNA (mtDNA)-enriched microparticles (MPs) than EAU without recent drinking (EAU - RD) and healthy controls, which correlated positively with circulating neutrophils...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724790/med12-regulates-a-transcriptional-network-of-calcium-handling-genes-in-the-heart
#17
Kedryn K Baskin, Catherine A Makarewich, Susan M DeLeon, Wenduo Ye, Beibei Chen, Nadine Beetz, Heinrich Schrewe, Rhonda Bassel-Duby, Eric N Olson
The Mediator complex regulates gene transcription by linking basal transcriptional machinery with DNA-bound transcription factors. The activity of the Mediator complex is mainly controlled by a kinase submodule that is composed of 4 proteins, including MED12. Although ubiquitously expressed, Mediator subunits can differentially regulate gene expression in a tissue-specific manner. Here, we report that MED12 is required for normal cardiac function, such that mice with conditional cardiac-specific deletion of MED12 display progressive dilated cardiomyopathy...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724789/red-blood-cell-%C3%AE-adrenergic-receptors-contribute-to-diet-induced-energy-expenditure-by-increasing-o2-supply
#18
Eun Ran Kim, Shengjie Fan, Dmitry Akhmedov, Kaiqi Sun, Hoyong Lim, William O'Brien, Yuanzhong Xu, Leandra R Mangieri, Yaming Zhu, Cheng-Chi Lee, Yeonseok Chung, Yang Xia, Yong Xu, Feng Li, Kai Sun, Rebecca Berdeaux, Qingchun Tong
Diet-induced obesity (DIO) represents the major cause for the current obesity epidemic, but the mechanism underlying DIO is unclear. β-Adrenergic receptors (β-ARs) play a major role in sympathetic nervous system-mediated (SNS-mediated) diet-induced energy expenditure (EE). Rbc express abundant β-ARs; however, a potential role for rbc in DIO remains untested. Here, we demonstrated that high-fat, high-caloric diet (HFD) feeding increased both EE and blood O2 content, and the HFD-induced increases in blood O2 level and in body weight gain were negatively correlated...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724788/multiparametric-immune-profiling-in-hpv-oral-squamous-cell-cancer
#19
Zipei Feng, Daniel Bethmann, Matthias Kappler, Carmen Ballesteros-Merino, Alexander Eckert, R Bryan Bell, Allen Cheng, Tuan Bui, Rom Leidner, Walter J Urba, Kent Johnson, Clifford Hoyt, Carlo B Bifulco, Juergen Bukur, Claudia Wickenhauser, Barbara Seliger, Bernard A Fox
Evaluation of T lymphocyte frequency provides prognostic information for patients with oral squamous cell cancer (OSCC). However, the effect of simultaneously evaluating T cell frequency and assessing suppressive elements and defects in antigen-processing machinery (APM) has not been clarified. Simultaneous characterization of CD3+, CD8+, FoxP3+, CD163+, and PD-L1+ cells using multispectral imaging was performed on sections from 119 patients with HPV- OSCC. Expression of β2-microglobulin, MHC class I heavy chain, and large multifunctional peptidase 10 was quantified, and all data were correlated with patient outcome...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724787/disrupted-apical-exocytosis-of-cargo-vesicles-causes-enteropathy-in-fhl5-patients-with-munc18-2-mutations
#20
Georg F Vogel, Jorik M van Rijn, Iris M Krainer, Andreas R Janecke, Carsten Posovzsky, Marta Cohen, Claire Searle, Prevost Jantchou, Johanna C Escher, Natalie Patey, Ernest Cutz, Thomas Müller, Sabine Middendorp, Michael W Hess, Lukas A Huber
Familial hemophagocytic lymphohistiocytosis 5 (FHL5) is an autosomal recessive disease caused by mutations in STXBP2, coding for Munc18-2, which is required for SNARE-mediated membrane fusion. FHL5 causes hematologic and gastrointestinal symptoms characterized by chronic enteropathy that is reminiscent of microvillus inclusion disease (MVID). However, the molecular pathophysiology of FHL5-associated diarrhea is poorly understood. Five FHL5 patients, including four previously unreported patients, were studied...
July 20, 2017: JCI Insight
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