Translational research : the journal of laboratory and clinical medicine
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In a process known as overt degranulation, mast cells can release all at once a diverse array of products that are preformed and present within cytoplasmic granules. This occurs typically within seconds of stimulation by environmental factors and allergens. These potent, preformed mediators (ie, histamine, heparin, serotonin, and serine proteases) are responsible for the acute symptoms experienced in allergic conditions such as allergic conjunctivitis, allergic rhinitis, allergy-induced asthma, urticaria, and anaphylaxis. ⋯ Mast cells can trigger actions and chemotaxis in other important immune cells (eg, eosinophils and the newly discovered type 2 innate lymphocytes) that then make their own contributions to inflammation and disease. In this review, we will discuss the many known and theorized contributions of mast cells to allergic diseases, focusing on several prototypical allergic respiratory and skin conditions: asthma, chronic rhinosinusitis, aspirin-exacerbated respiratory disease, allergic conjunctivitis, atopic dermatitis, and some of the more common medication hypersensitivity reactions. We discuss traditionally accepted roles that mast cells play in the pathogenesis of each of these conditions, but we also delve into new areas of discovery and research that challenge traditionally accepted paradigms.
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Proprotein convertase subtilisin kexin type 9 (PCSK9) belongs to the proprotein convertase family. Several studies have demonstrated its involvement in the regulation of low-density lipoprotein (LDL) cholesterol levels by inducing the degradation of the LDL receptor (LDLR). However, experimental, epidemiologic, and pharmacologic data provide important evidence on the role of PCSK9 also on high-density lipoproteins (HDLs). ⋯ Experimental studies demonstrated that PCSK9 directly interacts with HDL by modulating PCSK9 self-assembly and its binding to the LDLR. Finally, the inhibition of PCSK9 by means of monoclonal antibodies directed to PCSK9 (ie, evolocumab and alirocumab) determines an increase of HDL-C fraction by 7% and 4.2%, respectively. Thus, the understanding of the role of PCSK9 on HDL metabolism needs to be elucidated with a particular focus on the effect of PCSK9 on HDL-mediated reverse cholesterol transport.
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Sickle cell disease (SCD) afflicts millions of people worldwide and is associated with considerable morbidity and mortality. Chronic and acute vaso-occlusion are the clinical hallmarks of SCD and can result in pain crisis, widespread organ damage, and early movtality. Even though the molecular underpinnings of SCD were identified more than 60 years ago, there are no molecular or biophysical markers of disease severity that are feasibly measured in the clinic. ⋯ Here, we present a clinically applicable microfluidic device (SCD biochip) that allows serial quantitative evaluation of red blood cell (RBC) adhesion to endothelium-associated protein-immobilized microchannels, in a closed and preprocessing-free system. With the SCD biochip, we have analyzed blood samples from more than 100 subjects and have shown associations between the measured RBC adhesion to endothelium-associated proteins (fibronectin and laminin) and individual RBC characteristics, including hemoglobin content, fetal hemoglobin concentration, plasma lactate dehydrogenase level, and reticulocyte count. The SCD biochip is a functional adhesion assay, reflecting quantitative evaluation of RBC adhesion, which could be used at baseline, during crises, relative to various long-term complications, and before and after therapeutic interventions.
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Mechanical ventilation (MV) with hyperoxia is required for providing life support to patients with acute lung injury (ALI). However, MV may cause diaphragm weakness through muscle injury and atrophy, an effect termed ventilator-induced diaphragm dysfunction (VIDD). Src protein tyrosine kinase and class O of forkhead box 1 (FoxO1) mediate acute inflammatory responses and muscle protein degradation induced by oxidative stress. ⋯ MV during hyperoxia aggravated VIDD, as demonstrated by the increases in Src activation, FoxO1 dephosphorylation, malondialdehyde, caspase-3, atrogin-1 and muscle ring finger-1 production, microtubule-associated protein light chain 3-II, disorganized myofibrils, disrupted mitochondria, autophagy, and myonuclear apoptosis; however, MV with hyperoxia reduced mitochondrial cytochrome C, diaphragm muscle fiber size, and contractility (P < 0.05). Hyperoxia-exacerbated VIDD was attenuated in Src-deficient mice and by iPSCs and iPSC-CM (P < 0.05). Our data indicate that iPSC therapy attenuates MV-induced diaphragmatic injury that occurs during hyperoxia-augmented VIDD by inhibiting the Src-FoxO1 signaling pathway.
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Acute graft-versus-host disease (aGVHD), caused by donor T cell-mediated injury to host tissues, is a problem in allogeneic bone marrow transplantation. The transition from naïve to effector T cells is accompanied by shift in metabolism main pathway; from glucose oxidative phosphorylation to aerobic glycolysis. Adenosine monophosphate-activated protein kinase (AMPK) is a serine/threonine kinase that is a metabolic sensor that helps maintain cellular energy homeostasis. ⋯ Furthermore, metformin-treated Th17 cells became converted into Treg cells via enhanced autophagy. The reduction in mortality associated with metformin treatment was associated with inhibition of the mammalian target of rapamycin/signal transducer and activator of transcription 3 pathway. These results suggest that metformin might be of significant use in the treatment of patients with aGVHD.