Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease, with a worldwide prevalence of 25%. In the United States, NAFLD and its subtype, nonalcoholic steatohepatitis, affect 30% ...and 5% of the population, respectively. Considering the ongoing obesity epidemic beginning in childhood, the rise in diabetes, and other factors, the prevalence of NAFLD along with the proportion of those with advanced liver disease is projected to continue to increase. This will have an important impact on public health reflected in health care costs, including impact on the need for liver transplantation, for which nonalcoholic steatohepatitis is already close to becoming the most common indication. NAFLD patients with evidence of nonalcoholic steatohepatitis and advanced fibrosis are at markedly increased risk of adverse outcomes, including overall mortality, and liver-specific morbidity and mortality, respectively. Identification of this cohort of NAFLD patients is paramount, given the associated poorer outcomes, in order to target resources to those who need it most. Various noninvasive tools have been developed in this regard. This review provides an update on the epidemiology, clinical and prognostic features, and diagnostic approach to patients with NAFLD.
In multicellular organisms, the total number of cells is a balance between the cell-generating effects of mitosis and cell death that is induced through apoptosis. A disruption of this delicate ...balance can lead to the development of cancer. This Timeline article focuses on how the field of apoptosis biology has developed in the context of its contribution to our understanding of cell death, or lack of it, in the development of malignant disease. It traces the course of research from key discoveries in fundamental biology to potential therapeutic applications.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Reactive oxygen species (ROS) have been long regarded as by‐products of a cascade of reactions stemming from cellular oxygen metabolism, which, if they accumulate to toxic levels, can have ...detrimental effects on cellular biomolecules. However, more recently, the recognition of ROS as mediators of cellular communications has led to their classification as signalling mediators in their own right. The prototypic redox‐regulated targets downstream of ROS are the protein tyrosine phosphatases, and the wealth of research that has focused on this area has come to shape our understanding of how redox‐signalling contributes to and facilitates protein tyrosine phosphorylation signalling cascades. However, it is becoming increasingly apparent that there is more to this system than simply the negative regulation of protein tyrosine phosphatases. Identification of redox‐sensitive kinases such as Src led to the slow emergence of a role for redox regulation of tyrosine kinases. A flow of evidence, which has increased exponentially in recent times as a result of the development of new methods for the detection of oxidative modifications, demonstrates that, by concurrent oxidative activation of tyrosine kinases, ROS fine tune the duration and amplification of the phosphorylation signal. A more thorough understanding of the complex regulatory mechanism of redox‐modification will allow targeting of both the production of ROS and their downstream effectors for therapeutic purposes. The present review assesses the most relevant recent literature that demonstrates a role for kinase regulation by oxidation, highlights the most significant findings and proposes future directions for this crucial area of redox biology.
The recognition of ROS as mediators of cellular communications has led to their re‐classification as signalling molecules. Identification of redox‐sensitive kinases such as Src has prompted the emergence of a role for redox regulation of kinases. This review assesses the evidence for kinase regulation by direct oxidation, and proposes future directions for this crucial aspect of redox biology.
Emerging therapies for atopic dermatitis: JAK inhibitors Cotter, David G.; Schairer, David; Eichenfield, Lawrence
Journal of the American Academy of Dermatology,
March 2018, 2018-03-00, 20180301, Letnik:
78, Številka:
3
Journal Article
Recenzirano
The Janus kinase–signal transducer and activator of transcription pathway is a conserved master regulator of immunity and myeloproliferation. Advanced understanding of this pathway has led to ...development of targeted inhibitors of Janus kinases (Jakinibs). As a class, JAK inhibitors effectively treat a multitude of hematologic and inflammatory diseases. Given such success, use of JAK inhibitors for mitigation of atopic dermatitis is under active investigation. Herein, we review the evolving data on the safety and efficacy of JAK inhibitors in treatment of atopic dermatitis. Although it is still early in the study of JAK inhibitors for atopic dermatitis, evidence identifies JAK inhibitors as effective alternatives to conventional therapies. Nonetheless, multiple large safety and efficacy trials are needed before widespread use of JAK inhibitors can be advocated for atopic dermatitis.
Coronavirus Disease 2019 (COVID-19), caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has affected over 30 million globally to date. Although high rates of venous ...thromboembolism and evidence of COVID-19-induced endothelial dysfunction have been reported, the precise aetiology of the increased thrombotic risk associated with COVID-19 infection remains to be fully elucidated. Therefore, we assessed clinical platelet parameters and circulating platelet activity in patients with severe and nonsevere COVID-19. An assessment of clinical blood parameters in patients with severe COVID-19 disease (requiring intensive care), patients with nonsevere disease (not requiring intensive care), general medical in-patients without COVID-19, and healthy donors was undertaken. Platelet function and activity were also assessed by secretion and specific marker analysis. We demonstrated that routine clinical blood parameters including increased mean platelet volume (MPV) and decreased platelet:neutrophil ratio are associated with disease severity in COVID-19 upon hospitalisation and intensive care unit (ICU) admission. Strikingly, agonist-induced ADP release was 30- to 90-fold higher in COVID-19 patients compared with hospitalised controls and circulating levels of platelet factor 4 (PF4), soluble P-selectin (sP-selectin), and thrombopoietin (TPO) were also significantly elevated in COVID-19. This study shows that distinct differences exist in routine full blood count and other clinical laboratory parameters between patients with severe and nonsevere COVID-19. Moreover, we have determined all COVID-19 patients possess hyperactive circulating platelets. These data suggest abnormal platelet reactivity may contribute to hypercoagulability in COVID-19 and confirms the role that platelets/clotting has in determining the severity of the disease and the complexity of the recovery path.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Ketone body metabolism and cardiovascular disease Cotter, David G; Schugar, Rebecca C; Crawford, Peter A
American journal of physiology. Heart and circulatory physiology,
2013-Apr-15, Letnik:
304, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Ketone bodies are metabolized through evolutionarily conserved pathways that support bioenergetic homeostasis, particularly in brain, heart, and skeletal muscle when carbohydrates are in short ...supply. The metabolism of ketone bodies interfaces with the tricarboxylic acid cycle, β-oxidation of fatty acids, de novo lipogenesis, sterol biosynthesis, glucose metabolism, the mitochondrial electron transport chain, hormonal signaling, intracellular signal transduction pathways, and the microbiome. Here we review the mechanisms through which ketone bodies are metabolized and how their signals are transmitted. We focus on the roles this metabolic pathway may play in cardiovascular disease states, the bioenergetic benefits of myocardial ketone body oxidation, and prospective interactions among ketone body metabolism, obesity, metabolic syndrome, and atherosclerosis. Ketone body metabolism is noninvasively quantifiable in humans and is responsive to nutritional interventions. Therefore, further investigation of this pathway in disease models and in humans may ultimately yield tailored diagnostic strategies and therapies for specific pathological states.
ROS (reactive oxygen species) have long been regarded as a series of destructive molecules that have a detrimental effect on cell homoeostasis. In support of this are the myriad antioxidant defence ...systems nearly all eukaryotic cells have that are designed to keep the levels of ROS in check. However, research data emerging over the last decade have demonstrated that ROS can influence a range of cellular events in a manner similar to that seen for traditional second messenger molecules such as cAMP. Hydrogen peroxide (H2O2) appears to be the main ROS with such signalling properties, and this molecule has been shown to affect a wide range of cellular functions. Its localized synthesis by the Nox (NADPH oxidase) family of enzymes and how these enzymes are regulated is of particular interest to those who work in the field of tumour biology.
ROS signalling in the biology of cancer Moloney, Jennifer N.; Cotter, Thomas G.
Seminars in cell & developmental biology,
August 2018, 2018-08-00, 20180801, Letnik:
80
Journal Article
Recenzirano
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•Different types of tumour cells produce elevated levels of reactive oxygen species (ROS) compared to their normal counterparts.•Mitochondria and NADPH oxidases (NOX) are two major ...contributors of endogenous ROS in tumour cells.•The antioxidant capacity of tumour cells strives to scavenge excessive ROS while maintain pro-tumourigenic signalling and resistance to apoptosis.•Increased ROS levels can also activate anti-tumourigenic signalling resulting in oxidative stress induced-cancer cell death.•Specific modifications of ROS generation and antioxidant defences are identified as targets in cancer therapy.
Increased reactive oxygen species (ROS) production has been detected in various cancers and has been shown to have several roles, for example, they can activate pro-tumourigenic signalling, enhance cell survival and proliferation, and drive DNA damage and genetic instability. Counterintuitively ROS can also promote anti-tumourigenic signalling, initiating oxidative stress-induced tumour cell death. Tumour cells express elevated levels of antioxidant proteins to detoxify elevated ROS levels, establish a redox balance, while maintaining pro-tumourigenic signalling and resistance to apoptosis. Tumour cells have an altered redox balance to that of their normal counterparts and this identifies ROS manipulation as a potential target for cancer therapies. This review discusses the generation and sources of ROS within tumour cells, the regulation of ROS by antioxidant defence systems, as well as the effect of elevated ROS production on their signalling targets in cancer. It also provides an insight into how pro- and anti-tumourigenic ROS signalling pathways could be manipulated in the treatment of cancer.
Cells are constantly generating reactive oxygen species (ROS) during aerobic metabolism. As a consequence, each cell is equipped with an extensive antioxidant defence system to combat excessive ...production of ROS. Oxidative stress occurs in cells when the generation of ROS overwhelms the cell's natural antioxidant defences. There is a growing consensus that oxidative stress and the redox state of a cell plays a pivotal role in regulating apoptosis, a tightly controlled form of cell death in which a cell partakes in its own demise. More recently, a role for reactive nitrogen species (RNI) as both positive and negative regulators of cell death has been established. This review describes the major sources of ROS and RNI in a cell, the control of cell death by these species and the role of antioxidants as regulators of oxidative stress and apoptosis. Finally, the various methods that can be employed in establishing a role for both ROS and RNI in apoptosis will be discussed with particular emphasis on their intracellular detection.
Fermi has provided the largest sample of gamma -ray-selected blazars to date. In this work we use a uniformly selected set of 211 BL lacertae (BL Lac) objects detected by Fermi during its first year ...of operation. We obtained redshift constraints for 206 out of the 211 BL Lac objects in our sample, making it the largest and most complete sample of BL Lac objects available in the literature. We use this sample to determine the luminosity function of BL Lac objects and its evolution with cosmic time. We find that for most BL Lac classes the evolution is positive, with a space density peaking at modest redshift (z approximately 1.2). Low-luminosity, high-synchrotron-peaked (HSP) BL Lac objects are an exception, showing strong negative evolution, with number density increasing for z lap 0.5. Since this rise corresponds to a drop-off in the density of flat-spectrum radio quasars (FSRQs), a possible interpretation is that these HSPs represent an accretion-starved end state of an earlier merger-driven gas-rich phase. We additionally find that the known BL Lac correlation between luminosity and photon spectral index persists after correction for the substantial observational selection effects with implications for the so-called "blazar sequence." Finally, by estimating the beaming corrections to the luminosity function, we find that BL Lac objects have an average Lorentz factor of gamma = 6.1 super(+1.1) sub(-0.8), and that most are seen within 10degrees of the jet axis.
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