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Blood Apr 2011More than any other cytokine family, the IL-1 family of ligands and receptors is primarily associated with acute and chronic inflammation. The cytosolic segment of each... (Review)
Review
More than any other cytokine family, the IL-1 family of ligands and receptors is primarily associated with acute and chronic inflammation. The cytosolic segment of each IL-1 receptor family member contains the Toll-IL-1-receptor domain. This domain is also present in each Toll-like receptor, the receptors that respond to microbial products and viruses. Since Toll-IL-1-receptor domains are functional for both receptor families, responses to the IL-1 family are fundamental to innate immunity. Of the 11 members of the IL-1 family, IL-1β has emerged as a therapeutic target for an expanding number of systemic and local inflammatory conditions called autoinflammatory diseases. For these, neutralization of IL-1β results in a rapid and sustained reduction in disease severity. Treatment for autoimmune diseases often includes immunosuppressive drugs whereas neutralization of IL-1β is mostly anti-inflammatory. Although some autoinflammatory diseases are due to gain-of-function mutations for caspase-1 activity, common diseases such as gout, type 2 diabetes, heart failure, recurrent pericarditis, rheumatoid arthritis, and smoldering myeloma also are responsive to IL-1β neutralization. This review summarizes acute and chronic inflammatory diseases that are treated by reducing IL-1β activity and proposes that disease severity is affected by the anti-inflammatory members of the IL-1 family of ligands and receptors.
Topics: Animals; Autoimmune Diseases; Disease; Humans; Inflammation; Interleukin-1; Models, Biological; Molecular Targeted Therapy; Multigene Family; Receptors, Interleukin-1; Toll-Like Receptors
PubMed: 21304099
DOI: 10.1182/blood-2010-07-273417 -
Clinical Pharmacology and Therapeutics Dec 2012Molecular medicine is moving beyond genomics to encompass the new scientific field of epigenetics. First described as a conceptual model of how genes might interact with...
Molecular medicine is moving beyond genomics to encompass the new scientific field of epigenetics. First described as a conceptual model of how genes might interact with their surroundings to produce a phenotype, epigenomic research currently investigates mechanisms of nongenetic modification contributing to gene regulation and examines the impact of these changes on human health and behavior.
Topics: Animals; Disease; Drug Discovery; Epigenesis, Genetic; Epigenomics; Gene-Environment Interaction; Humans; Pharmacology; Research
PubMed: 23160355
DOI: 10.1038/clpt.2012.179 -
Molecular Biotechnology Sep 2007Cells are continuously exposed to reactive oxygen species (ROS) generated by aerobic metabolism. Excessively generated ROS causes severe dysfunctions to cells as... (Review)
Review
Cells are continuously exposed to reactive oxygen species (ROS) generated by aerobic metabolism. Excessively generated ROS causes severe dysfunctions to cells as oxidative stress. On the other hand, there is increasing evidence that ROS plays important roles as a signaling intermediate that induces a wide variety of cellular responses such as proliferation, differentiation, senescence, and apoptosis. To transmit physiological ROS-mediated signals and to adapt to oxidative stress, cells are equipped with various intracellular signal transduction systems, represented by mitogen-activated protein kinase (MAPK) cascades. Apoptosis signal-regulating kinase 1 (ASK1) is an upstream regulator of the stress-activated MAPK cascades and has been shown to play critical roles in ROS-mediated cellular responses. Here, we highlight the roles of members of the ASK family, which consists of ASK1 and newly characterized ASK2, in ROS signaling with their possible involvement in human diseases.
Topics: Animals; Disease; Humans; MAP Kinase Kinase Kinase 5; MAP Kinase Kinase Kinases; Oxidative Stress; Reactive Oxygen Species
PubMed: 17914158
DOI: 10.1007/s12033-007-0053-x -
Essays in Biochemistry Sep 2023Today, it is accepted that the ability to evade the attention of the immune system is an essential hallmark of cancer. Critically, as tumours progress, cancer cells can...
Today, it is accepted that the ability to evade the attention of the immune system is an essential hallmark of cancer. Critically, as tumours progress, cancer cells can protect themselves from the immune system's natural ability to fight the disease. This observation has led to an explosion of basic research to discover how to restore anti-tumour immunity for advancing cancer treatment. Clinical successes have been achieved following the approval of checkpoint inhibitor therapy to effectively prolong the life of many cancer patients with malignant disease. However, despite impressive survival gains, there is still a high variability of responses between different types of cancer and many patients still fail to respond. The disappointing findings that have been documented over the many clinical trials performed so far coincide with a much more complex view of immuno-oncology that has emerged from technological advances in functional fluorescent imaging techniques, high-throughput RNA sequencing and single-cell mass cytometry. The themed topic 'Immuno-Oncology' captures the contemporary understanding that individual tumours comprise remarkable mixtures of immune cell populations that actively contribute to neoplastic growth, invasion and metastasis through reciprocal and dynamic interactions with cancer cells. In the context of this new knowledge, the reviews discuss novel ideas of therapeutic opportunities for cancer. We would like to thank the authors for their excellent contributions.
Topics: Humans; Neoplasms; Syndrome
PubMed: 37767785
DOI: 10.1042/EBC20230071 -
Nature Reviews. Immunology Jul 2011Neutrophils have long been viewed as the final effector cells of an acute inflammatory response, with a primary role in the clearance of extracellular pathogens.... (Review)
Review
Neutrophils have long been viewed as the final effector cells of an acute inflammatory response, with a primary role in the clearance of extracellular pathogens. However, more recent evidence has extended the functions of these cells. The newly discovered repertoire of effector molecules in the neutrophil armamentarium includes a broad array of cytokines, extracellular traps and effector molecules of the humoral arm of the innate immune system. In addition, neutrophils are involved in the activation, regulation and effector functions of innate and adaptive immune cells. Accordingly, neutrophils have a crucial role in the pathogenesis of a broad range of diseases, including infections caused by intracellular pathogens, autoimmunity, chronic inflammation and cancer.
Topics: Adaptive Immunity; Animals; Disease; Humans; Immunity, Innate; Neutrophils
PubMed: 21785456
DOI: 10.1038/nri3024 -
Cold Spring Harbor Symposia on... 2011All organisms sense and respond to environmental and physiological stress by inducing cell stress responses that protect core biosynthetic processes such as DNA repair,... (Review)
Review
All organisms sense and respond to environmental and physiological stress by inducing cell stress responses that protect core biosynthetic processes such as DNA repair, protein folding, and clearance of damaged proteins. Of these, the heat shock response (HSR) protects the proteome against acute exposure to elevated temperatures, oxidants, and heavy metals, for example, and to the chronic expression of metastable, aggregation-prone proteins associated with aging and diseases of protein conformation. Induction of the HSR leads to the rapid and robust expression of molecular chaperones and other cell-protective pathways to protect nascent chain synthesis and folding, to prevent misfolding and aggregation, and to promote recovery from stress-induced damage. This review examines the properties of the stress-responsive transcription factor, HSF-1, in the regulation of the HSR, our current understanding of the stress-sensing mechanisms that recognize and distinguish between acute stress such as heat shock and chronic proteostasis imbalance as occurs in neurodegenerative diseases, and the cell nonautonomous control of the HSR by neuronal signaling in metazoans. This complex, systems-wide interdependence ensures cellular health span and organismal life span.
Topics: Aging; Animals; Disease; Heat-Shock Response; Humans; Proteins; Stress, Physiological; Systems Biology
PubMed: 22371371
DOI: 10.1101/sqb.2012.76.010637 -
Frontiers in Immunology 2023Sepsis is a hyper-heterogeneous syndrome in which the systemic inflammatory response persists throughout the course of the disease and the inflammatory and immune... (Review)
Review
Sepsis is a hyper-heterogeneous syndrome in which the systemic inflammatory response persists throughout the course of the disease and the inflammatory and immune responses are dynamically altered at different pathogenic stages. Gasdermins (GSDMs) proteins are pore-forming executors in the membrane, subsequently mediating the release of pro-inflammatory mediators and inflammatory cell death. With the increasing research on GSDMs proteins and sepsis, it is believed that GSDMs protein are one of the most promising therapeutic targets in sepsis in the future. A more comprehensive and in-depth understanding of the functions of GSDMs proteins in sepsis is important to alleviate the multi-organ dysfunction and reduce sepsis-induced mortality. In this review, we focus on the function of GSDMs proteins, the molecular mechanism of GSDMs involved in sepsis, and the regulatory mechanism of GSDMs-mediated signaling pathways, aiming to provide novel ideas and therapeutic strategies for the diagnosis and treatment of sepsis.
Topics: Humans; Gasdermins; Sepsis; Cell Death; Inflammation Mediators; Syndrome
PubMed: 38022612
DOI: 10.3389/fimmu.2023.1203687 -
Cell Feb 2009Cellular functions depend on numerous protein-coding and noncoding RNAs and the RNA-binding proteins associated with them, which form ribonucleoprotein complexes (RNPs).... (Review)
Review
Cellular functions depend on numerous protein-coding and noncoding RNAs and the RNA-binding proteins associated with them, which form ribonucleoprotein complexes (RNPs). Mutations that disrupt either the RNA or protein components of RNPs or the factors required for their assembly can be deleterious. Alternative splicing provides cells with an exquisite capacity to fine-tune their transcriptome and proteome in response to cues. Splicing depends on a complex code, numerous RNA-binding proteins, and an enormously intricate network of interactions among them, increasing the opportunity for exposure to mutations and misregulation that cause disease. The discovery of disease-causing mutations in RNAs is yielding a wealth of new therapeutic targets, and the growing understanding of RNA biology and chemistry is providing new RNA-based tools for developing therapeutics.
Topics: Alternative Splicing; Disease; Mutation; RNA; RNA Splicing; Therapeutics
PubMed: 19239895
DOI: 10.1016/j.cell.2009.02.011 -
Nucleic Acids Research Jan 2018Enhancers, as specialized genomic cis-regulatory elements, activate transcription of their target genes and play an important role in pathogenesis of many human complex...
Enhancers, as specialized genomic cis-regulatory elements, activate transcription of their target genes and play an important role in pathogenesis of many human complex diseases. Despite recent systematic identification of them in the human genome, currently there is an urgent need for comprehensive annotation databases of human enhancers with a focus on their disease connections. In response, we built the Human Enhancer Disease Database (HEDD) to facilitate studies of enhancers and their potential roles in human complex diseases. HEDD currently provides comprehensive genomic information for ∼2.8 million human enhancers identified by ENCODE, FANTOM5 and RoadMap with disease association scores based on enhancer-gene and gene-disease connections. It also provides Web-based analytical tools to visualize enhancer networks and score enhancers given a set of selected genes in a specific gene network. HEDD is freely accessible at http://zdzlab.einstein.yu.edu/1/hedd.php.
Topics: Chromosomes, Human, Pair 9; Databases, Nucleic Acid; Disease; Enhancer Elements, Genetic; Gene Regulatory Networks; Genome, Human; Genome-Wide Association Study; Humans; Internet; Molecular Sequence Annotation; Multifactorial Inheritance; Polymorphism, Single Nucleotide
PubMed: 29077884
DOI: 10.1093/nar/gkx988 -
Nature Medicine Jun 2023Alcohol consumption accounts for ~3 million annual deaths worldwide, but uncertainty persists about its relationships with many diseases. We investigated the...
Alcohol consumption accounts for ~3 million annual deaths worldwide, but uncertainty persists about its relationships with many diseases. We investigated the associations of alcohol consumption with 207 diseases in the 12-year China Kadoorie Biobank of >512,000 adults (41% men), including 168,050 genotyped for ALDH2- rs671 and ADH1B- rs1229984 , with >1.1 million ICD-10 coded hospitalized events. At baseline, 33% of men drank alcohol regularly. Among men, alcohol intake was positively associated with 61 diseases, including 33 not defined by the World Health Organization as alcohol-related, such as cataract (n = 2,028; hazard ratio 1.21; 95% confidence interval 1.09-1.33, per 280 g per week) and gout (n = 402; 1.57, 1.33-1.86). Genotype-predicted mean alcohol intake was positively associated with established (n = 28,564; 1.14, 1.09-1.20) and new alcohol-associated (n = 16,138; 1.06, 1.01-1.12) diseases, and with specific diseases such as liver cirrhosis (n = 499; 2.30, 1.58-3.35), stroke (n = 12,176; 1.38, 1.27-1.49) and gout (n = 338; 2.33, 1.49-3.62), but not ischemic heart disease (n = 8,408; 1.04, 0.94-1.14). Among women, 2% drank alcohol resulting in low power to assess associations of self-reported alcohol intake with disease risks, but genetic findings in women suggested the excess male risks were not due to pleiotropic genotypic effects. Among Chinese men, alcohol consumption increased multiple disease risks, highlighting the need to strengthen preventive measures to reduce alcohol intake.
Topics: Adult; Female; Humans; Male; Alcohol Drinking; Aldehyde Dehydrogenase, Mitochondrial; East Asian People; Ethanol; Genotype; Gout; Risk Factors; Disease; China
PubMed: 37291211
DOI: 10.1038/s41591-023-02383-8