Review

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease that is associated with aberrant activation of TGF-β, myofibroblast differentiation, and abnormal extracellular matrix (ECM) production. Proper regulation of protein stability is important for maintenance of intracellular protein homeostasis and signaling. Ubiquitin E3 ligases mediate protein ubiquitination, and deubiquitinating enzymes (DUBs) reverse the process. The role of ubiquitin E3 ligases and DUBs in the pathogenesis of IPF is relatively unexplored. In this review, we provide an overview of how ubiquitin E3 ligases and DUBs modulate pulmonary fibrosis through regulation of both TGF-β–dependent and –independent pathways. We also summarize currently available small-molecule inhibitors of ubiquitin E3 ligases and DUBs as potential therapeutic strategies for the treatment of IPF.

Authors

Shuang Li, Jing Zhao, Dong Shang, Daniel J. Kass, Yutong Zhao

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Abstract

Extracellular RNA (exRNA) has emerged as an important transducer of intercellular communication. Advancing exRNA research promises to revolutionize biology and transform clinical practice. Recent efforts have led to cutting-edge research and expanded knowledge of this new paradigm in cell-to-cell crosstalk; however, gaps in our understanding of EV heterogeneity and exRNA diversity pose significant challenges for continued development of exRNA diagnostics and therapeutics. To unravel this complexity, the NIH convened expert teams to discuss the current state of the science, define the significant bottlenecks, and brainstorm potential solutions across the entire exRNA research field. The NIH Strategic Workshop on Extracellular RNA Transport helped identify mechanistic and clinical research opportunities for exRNA biology and provided recommendations on high priority areas of research that will advance the exRNA field.

Authors

Kang Li, Rodosthenis S. Rodosthenous, Fatah Kashanchi, Thomas Gingeras, Stephen J. Gould, Lillian S. Kuo, Peter Kurre, Hakho Lee, Joshua N. Leonard, Huiping Liu, Tania B. Lombo, Stefan Momma, John P. Nolan, Margaret J. Ochocinska, D. Michiel Pegtel, Yoel Sadovsky, Francisco Sánchez-Madrid, Kayla M. Valdes, Kasey C. Vickers, Alissa M. Weaver, Kenneth W. Witwer, Yong Zeng, Saumya Das, Robert L. Raffai, T. Kevin Howcroft

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Abstract

The emergence of community-associated methicillin-resistant Staphylococcus aureus during the past decade along with an impending shortage of effective antistaphylococcal antibiotics have fueled impressive advances in our understanding of how S. aureus overcomes the host environment to establish infection. Backed by recent technologic advances, studies have uncovered elaborate metabolic, nutritional, and virulence strategies deployed by S. aureus to survive the restrictive and hostile environment imposed by the host, leading to a plethora of promising antimicrobial approaches that have potential to remedy the antibiotic resistance crisis. In this Review, we highlight some of the critical and recently elucidated bacterial strategies that are potentially amenable to intervention, discuss their relevance to human diseases, and address the translational challenges posed by current animal models.

Authors

Isaac P. Thomsen, George Y. Liu

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Abstract

Mild traumatic brain injury (mTBI) is a common occurrence, with over 3 million cases reported every year in the United States. While research into the underlying pathophysiology is ongoing, there is an urgent need for better clinical guidelines that allow more consistent diagnosis of mTBI and ensure safe return-to-play timelines for athletes, nonathletes, and military personnel. The development of a suite of biomarkers that indicate the pathogenicity of mTBI could lead to clinically useful tools for establishing both diagnosis and prognosis. Here, we review the current evidence for mTBI biomarkers derived from investigations of the multifactorial pathology of mTBI. While the current literature lacks the scope and size for clarification of these biomarkers’ clinical utility, early studies have identified some promising candidates.

Authors

Han Jun Kim, Jack W. Tsao, Ansley Grimes Stanfill

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Abstract

Cirrhosis is a prevalent cause of morbidity and mortality, especially for those at an advanced decompensated stage. Cirrhosis development and progression involves several important interorgan communications, and recently, the gut microbiome has been implicated in pathophysiology of the disease. Dysbiosis, defined as a pathological change in the microbiome, has a variable effect on the compensated versus decompensated stage of cirrhosis. Adverse microbial changes, both in composition and function, can act at several levels within the gut (stool and mucosal) and have also been described in the blood and oral cavity. While dysbiosis in the oral cavity could be a source of systemic inflammation, current cirrhosis treatment modalities are targeted toward the gut-liver axis and do not address the oral microbiome. As interventions designed to modulate oral dysbiosis may delay progression of cirrhosis, a better understanding of this process is of the utmost importance. The concept of oral microbiota dysbiosis in cirrhosis is relatively new; therefore, this review will highlight the emerging role of the oral-gut-liver axis and introduce perspectives for future research.

Authors

Chathur Acharya, Sinem Esra Sahingur, Jasmohan S. Bajaj

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Abstract

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a poor outcome; overall survival is approximately 35% at two years and some subgroups have a less than 5% two-year survival. Recently, significant improvements have been made in our understanding of AML biology and genetics. These fundamental discoveries are now being translated into new therapies for this disease. This review will discuss recent advances in AML biology and the emerging treatments that are arising from biological studies. Specifically, we will consider new therapies that target molecular mutations in AML and dysregulated pathways such as apoptosis and mitochondrial metabolism. We will also discuss recent advances in immune and cellular therapy for AML.

Authors

Simon Kavanagh, Tracy Murphy, Arjun Law, Dana Yehudai, Jenny M. Ho, Steve Chan, Aaron D. Schimmer

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Abstract

Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are among the most frequent causes of chronic liver disease in the United States. Although the two entities are triggered by different etiologies — chronic alcohol consumption (ASH) and obesity-associated lipotoxicity (NASH) — they share overlapping histological and clinical features owing to common pathogenic mechanisms. These pathogenic processes include altered hepatocyte lipid metabolism, organelle dysfunction (i.e., ER stress), hepatocyte apoptosis, innate immune system activation, and hepatic stellate cell activation. Nonetheless, there are several disease-specific molecular signaling pathways, such as differential pathway activation downstream of TLR4 (MyD88-dependence in NASH versus MyD88-independence in ASH), inflammasome activation and IL-1β signaling in ASH, insulin resistance and lipotoxicity in NASH, and dysregulation of different microRNAs, which clearly highlight that ASH and NASH are two distinct biological entities. Both pathogenic similarities and differences have therapeutic implications. In this Review, we discuss these pathogenic mechanisms and their therapeutic implications for each disease, focusing on both shared and distinct targets.

Authors

Thomas Greuter, Harmeet Malhi, Gregory J. Gores, Vijay H. Shah

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Abstract

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. This knowledge is leading to identification of new targets and therapeutic strategies for preventing or reversing retinal neuronal dysfunction, vascular leakage, ischemia, and pathologic angiogenesis. These advances, together with approaches embracing the potential of preventative or regenerative medicine, could provide the means to better manage DR, including treatment at earlier stages and more precise tailoring of treatments based on individual patient variations.

Authors

Elia J. Duh, Jennifer K. Sun, Alan W. Stitt

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Abstract

Pathogenic fungi cause a wide range of syndromes in immune-competent and immune-compromised individuals, with life-threatening disease primarily seen in humans with HIV/AIDS and in patients receiving immunosuppressive therapies for cancer, autoimmunity, and end-organ failure. The discovery that specific primary immune deficiencies manifest with fungal infections and the development of animal models of mucosal and invasive mycoses have facilitated insight into fungus-specific recognition, signaling, effector pathways, and adaptive immune responses. Progress in deciphering the molecular and cellular basis of immunity against fungi is guiding preclinical studies into vaccine and immune reconstitution strategies for vulnerable patient groups. Furthermore, recent work has begun to address the role of endogenous fungal communities in human health and disease. In this review, we summarize a contemporary understanding of protective immunity against fungi.

Authors

Michail S. Lionakis, Iliyan D. Iliev, Tobias M. Hohl

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Abstract

Lung transplantation, a cure for a number of end-stage lung diseases, continues to have the worst long-term outcomes when compared with other solid organ transplants. Preclinical modeling of the most common and serious lung transplantation complications are essential to better understand and mitigate the pathophysiological processes that lead to these complications. Various animal and in vitro models of lung transplant complications now exist and each of these models has unique strengths. However, significant issues, such as the required technical expertise as well as the robustness and clinical usefulness of these models, remain to be overcome or clarified. The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop in March 2016 to review the state of preclinical science addressing the three most important complications of lung transplantation: primary graft dysfunction (PGD), acute rejection (AR), and chronic lung allograft dysfunction (CLAD). In addition, the participants of the workshop were tasked to make consensus recommendations on the best use of these complimentary models to close our knowledge gaps in PGD, AR, and CLAD. Their reviews and recommendations are summarized in this report. Furthermore, the participants outlined opportunities to collaborate and directions to accelerate research using these preclinical models.

Authors

Vibha N. Lama, John A. Belperio, Jason D. Christie, Souheil El-Chemaly, Michael C. Fishbein, Andrew E. Gelman, Wayne W. Hancock, Shaf Keshavjee, Daniel Kreisel, Victor E. Laubach, Mark R. Looney, John F. McDyer, Thalachallour Mohanakumar, Rebecca A. Shilling, Angela Panoskaltsis-Mortari, David S. Wilkes, Jerry P. Eu, Mark R. Nicolls

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