Inflammasome activation and caspase-1–dependent (CASP1-dependent) processing and secretion of IL-1β and IL-18 are critical events at the interface of the bacterial pathogen
Katrin N. Koch, Mara L. Hartung, Sabine Urban, Andreas Kyburz, Anna S. Bahlmann, Judith Lind, Steffen Backert, Christian Taube, Anne Müller
Uterine leiomyomas are benign tumors that can cause pain, bleeding, and infertility in some women. Mediator complex subunit 12 (
Priya Mittal, Yong-hyun Shin, Svetlana A. Yatsenko, Carlos A. Castro, Urvashi Surti, Aleksandar Rajkovic
Alcoholism, or alcohol use disorder, is a major public health concern that is a considerable risk factor for morbidity and disability; therefore, effective treatments are urgently needed. Here, we demonstrated that the glucocorticoid receptor (GR) antagonist mifepristone reduces alcohol intake in alcohol-dependent rats but not in nondependent animals. Both systemic delivery and direct administration into the central nucleus of the amygdala, a critical stress-related brain region, were sufficient to reduce alcohol consumption in dependent animals. We also tested the use of mifepristone in 56 alcohol-dependent human subjects as part of a double-blind clinical and laboratory-based study. Relative to placebo, individuals who received mifepristone (600 mg daily taken orally for 1 week) exhibited a substantial reduction in alcohol-cued craving in the laboratory, and naturalistic measures revealed reduced alcohol consumption during the 1-week treatment phase and 1-week post-treatment phase in mifepristone-treated individuals. Mifepristone was well tolerated and improved liver-function markers. Together, these results support further exploration of GR antagonism via mifepristone as a therapeutic strategy for alcoholism.
Leandro F. Vendruscolo, David Estey, Vivian Goodell, Lauren G. Macshane, Marian L. Logrip, Joel E. Schlosburg, M. Adrienne McGinn, Eva R. Zamora-Martinez, Joseph K. Belanoff, Hazel J. Hunt, Pietro P. Sanna, Olivier George, George F. Koob, Scott Edwards, Barbara J. Mason
Despite the wide availability of antiretroviral drugs, more than 250,000 infants are vertically infected with HIV-1 annually, emphasizing the need for additional interventions to eliminate pediatric HIV-1 infections. Here, we aimed to define humoral immune correlates of risk of mother-to-child transmission (MTCT) of HIV-1, including responses associated with protection in the RV144 vaccine trial. Eighty-three untreated, HIV-1–transmitting mothers and 165 propensity score–matched nontransmitting mothers were selected from the Women and Infants Transmission Study (WITS) of US nonbreastfeeding, HIV-1–infected mothers. In a multivariable logistic regression model, the magnitude of the maternal IgG responses specific for the third variable loop (V3) of the HIV-1 envelope was predictive of a reduced risk of MTCT. Neutralizing Ab responses against easy-to-neutralize (tier 1) HIV-1 strains also predicted a reduced risk of peripartum transmission in secondary analyses. Moreover, recombinant maternal V3–specific IgG mAbs mediated neutralization of autologous HIV-1 isolates. Thus, common V3-specific Ab responses in maternal plasma predicted a reduced risk of MTCT and mediated autologous virus neutralization, suggesting that boosting these maternal Ab responses may further reduce HIV-1 MTCT.
Sallie R. Permar, Youyi Fong, Nathan Vandergrift, Genevieve G. Fouda, Peter Gilbert, Robert Parks, Frederick H. Jaeger, Justin Pollara, Amanda Martelli, Brooke E. Liebl, Krissey Lloyd, Nicole L. Yates, R. Glenn Overman, Xiaoying Shen, Kaylan Whitaker, Haiyan Chen, Jamie Pritchett, Erika Solomon, Emma Friberg, Dawn J. Marshall, John F. Whitesides, Thaddeus C. Gurley, Tarra Von Holle, David R. Martinez, Fangping Cai, Amit Kumar, Shi-Mao Xia, Xiaozhi Lu, Raul Louzao, Samantha Wilkes, Saheli Datta, Marcella Sarzotti-Kelsoe, Hua-Xin Liao, Guido Ferrari, S. Munir Alam, David C. Montefiori, Thomas N. Denny, M. Anthony Moody, Georgia D. Tomaras, Feng Gao, Barton F. Haynes
The generation of potent opioid analgesics that lack the side effects of traditional opioids may be possible by targeting truncated splice variants of the μ-opioid receptor. μ-Opioids act through GPCRs that are generated from the
Zhigang Lu, Jin Xu, Grace C. Rossi, Susruta Majumdar, Gavril W. Pasternak, Ying-Xian Pan
Transfusion of donor-derived platelets is commonly used for thrombocytopenia, which results from a variety of clinical conditions and relies on a constant donor supply due to the limited shelf life of these cells. Embryonic stem (ES) and induced pluripotent stem (iPS) cells represent a potential source of megakaryocytes and platelets for transfusion therapies; however, the majority of current ES/iPS cell differentiation protocols are limited by low yields of hematopoietic progeny. In both mice and humans, mutations in the gene-encoding transcription factor GATA1 cause an accumulation of proliferating, developmentally arrested megakaryocytes, suggesting that GATA1 suppression in ES and iPS cell–derived hematopoietic progenitors may enhance megakaryocyte production. Here, we engineered ES cells from WT mice to express a doxycycline-regulated (dox-regulated) shRNA that targets
Ji-Yoon Noh, Shilpa Gandre-Babbe, Yuhuan Wang, Vincent Hayes, Yu Yao, Paul Gadue, Spencer K. Sullivan, Stella T. Chou, Kellie R. Machlus, Joseph E. Italiano Jr., Michael Kyba, David Finkelstein, Jacob C. Ulirsch, Vijay G. Sankaran, Deborah L. French, Mortimer Poncz, Mitchell J. Weiss
A transition from fetal hemoglobin (HbF) to adult hemoglobin (HbA) normally occurs within a few months after birth. Increased production of HbF after this period of infancy ameliorates clinical symptoms of the major disorders of adult β-hemoglobin: β-thalassemia and sickle cell disease. The transcription factor BCL11A silences HbF and has been an attractive therapeutic target for increasing HbF levels; however, it is not clear to what extent BCL11A inhibits HbF production or mediates other developmental functions in humans. Here, we identified and characterized 3 patients with rare microdeletions of 2p15-p16.1 who presented with an autism spectrum disorder and developmental delay. Moreover, these patients all exhibited substantial persistence of HbF but otherwise retained apparently normal hematologic and immunologic function. Of the genes within 2p15-p16.1, only
Anindita Basak, Miroslava Hancarova, Jacob C. Ulirsch, Tugce B. Balci, Marie Trkova, Michal Pelisek, Marketa Vlckova, Katerina Muzikova, Jaroslav Cermak, Jan Trka, David A. Dyment, Stuart H. Orkin, Mark J. Daly, Zdenek Sedlacek, Vijay G. Sankaran
The cGMP-dependent protein kinase-1α (PKG1α) transduces NO and natriuretic peptide signaling; therefore, PKG1α activation can benefit the failing heart. Disease modifiers such as oxidative stress may depress the efficacy of PKG1α pathway activation and underlie variable clinical results. PKG1α can also be directly oxidized, forming a disulfide bond between homodimer subunits at cysteine 42 to enhance oxidant-stimulated vasorelaxation; however, the impact of PKG1α oxidation on myocardial regulation is unknown. Here, we demonstrated that PKG1α is oxidized in both patients with heart disease and in rodent disease models. Moreover, this oxidation contributed to adverse heart remodeling following sustained pressure overload or Gq agonist stimulation. Compared with control hearts and myocytes, those expressing a redox-dead protein (PKG1αC42S) better adapted to cardiac stresses at functional, histological, and molecular levels. Redox-dependent changes in PKG1α altered intracellular translocation, with the activated, oxidized form solely located in the cytosol, whereas reduced PKG1αC42S translocated to and remained at the outer plasma membrane. This altered PKG1α localization enhanced suppression of transient receptor potential channel 6 (TRPC6), thereby potentiating antihypertrophic signaling. Together, these results demonstrate that myocardial PKG1α oxidation prevents a beneficial response to pathological stress, may explain variable responses to PKG1α pathway stimulation in heart disease, and indicate that maintaining PKG1α in its reduced form may optimize its intrinsic cardioprotective properties.
Taishi Nakamura, Mark J. Ranek, Dong I. Lee, Virginia Shalkey Hahn, Choel Kim, Philip Eaton, David A. Kass
Epidemiological studies show that patients with type-2-diabetes (T2DM) and individuals with a diabetes-independent elevation in blood glucose have an increased risk for developing dementia, specifically dementia due to Alzheimer’s disease (AD). These observations suggest that abnormal glucose metabolism likely plays a role in some aspects of AD pathogenesis, leading us to investigate the link between aberrant glucose metabolism, T2DM, and AD in murine models. Here, we combined two techniques — glucose clamps and in vivo microdialysis — as a means to dynamically modulate blood glucose levels in awake, freely moving mice while measuring real-time changes in amyloid-β (Aβ), glucose, and lactate within the hippocampal interstitial fluid (ISF). In a murine model of AD, induction of acute hyperglycemia in young animals increased ISF Aβ production and ISF lactate, which serves as a marker of neuronal activity. These effects were exacerbated in aged AD mice with marked Aβ plaque pathology. Inward rectifying, ATP-sensitive potassium (KATP) channels mediated the response to elevated glucose levels, as pharmacological manipulation of KATP channels in the hippocampus altered both ISF Aβ levels and neuronal activity. Taken together, these results suggest that KATP channel activation mediates the response of hippocampal neurons to hyperglycemia by coupling metabolism with neuronal activity and ISF Aβ levels.
Shannon L. Macauley, Molly Stanley, Emily E. Caesar, Steven A. Yamada, Marcus E. Raichle, Ronaldo Perez, Thomas E. Mahan, Courtney L. Sutphen, David M. Holtzman
Cigarette smoke (CS) and viruses promote the inflammation and remodeling associated with chronic obstructive pulmonary disease (COPD). The MAVS/RIG-I–like helicase (MAVS/RLH) pathway and inflammasome-dependent innate immune pathways are important mediators of these responses. At baseline, the MAVS/RLH pathway is suppressed, and this inhibition must be reversed to engender tissue effects; however, the mechanisms that mediate activation and repression of the pathway have not been defined. In addition, the regulation and contribution of MAVS/RLH signaling in CS-induced inflammation and remodeling responses and in the development of human COPD remain unaddressed. Here, we demonstrate that expression of NLRX1, which inhibits the MAVS/RLH pathway and regulates other innate immune responses, was markedly decreased in 3 independent cohorts of COPD patients. NLRX1 suppression correlated directly with disease severity and inversely with pulmonary function, quality of life, and prognosis. In murine models, CS inhibited NLRX1, and CS-induced inflammation, alveolar destruction, protease induction, structural cell apoptosis, and inflammasome activation were augmented in NLRX1-deficient animals. Conversely, MAVS deficiency abrogated this CS-induced inflammation and remodeling. Restoration of NLRX1 in CS-exposed animals ameliorated alveolar destruction. These data support a model in which CS-dependent NLRX1 inhibition facilitates MAVS/RHL activation and subsequent inflammation, remodeling, protease, cell death, and inflammasome responses.
Min-Jong Kang, Chang Min Yoon, Bo Hye Kim, Chang-Min Lee, Yang Zhou, Maor Sauler, Rober Homer, Anish Dhamija, Daniel Boffa, Andrew Phillip West, Gerald S. Shadel, Jenny P. Ting, John R. Tedrow, Naftali Kaminski, Woo Jin Kim, Chun Geun Lee, Yeon-Mok Oh, Jack A. Elias
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