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1.
Osteoarthritis Cartilage ; 25(12): 2091-2099, 2017 12.
Article in English | MEDLINE | ID: mdl-28882752

ABSTRACT

OBJECTIVE: Osteoarthritis (OA) is a disabling and highly prevalent condition affecting millions worldwide. Pain is the major complaint of OA patients and is presently inadequately managed. It manifests as mechanical allodynia, a painful response to innocuous stimuli such as joint movement. Allodynia is due in part to the sensitization of articular nociceptors to mechanical stimuli. These nociceptors respond to noxious mechanical stimuli applied to their terminals via the expression of depolarizing high-threshold mechanosensitive ion channels (MSICs) that convert painful mechanical forces into electrical signals. In this study, we examined the contribution of MSICs to mechanical allodynia in a mouse model of OA. METHOD: Sodium mono-iodoacetate (MIA) was injected in the left knee of adult male Trpv1:Cre; GFP mice. Primary mechanical allodynia was monitored using the knee-bend test. Single-channel patch clamp electrophysiology was performed on visually-identified knee-innervating nociceptors. Dorsal horn neuronal activation was assessed by Fos immunoreactivity. RESULTS: In examining the gating properties of MSICs of naïve and OA mice, we discovered that their activation threshold is greatly reduced, causing their opening at significantly lower stimuli intensities. Consequently, nociceptors are activated by mild mechanical stimuli. These channels are reversibly inhibited by the selective MSIC inhibitor GsMTx4, and the intra-articular injection of this peptide significantly reduced the activation of dorsal horn nociceptive circuits and primary mechanical allodynia in OA mice. CONCLUSIONS: These results suggest that MSICs are sensitized during OA and directly contribute to mechanical allodynia. They therefore represent potential therapeutic targets in the treatment of OA pain.


Subject(s)
Enzyme Inhibitors/pharmacology , Hyperalgesia/metabolism , Iodoacetic Acid/pharmacology , Ion Channels/drug effects , Nociception/drug effects , Nociceptors/drug effects , Osteoarthritis, Knee/metabolism , Posterior Horn Cells/drug effects , Animals , Hyperalgesia/physiopathology , Injections, Intra-Articular , Ion Channels/metabolism , Male , Mechanotransduction, Cellular , Mice , Nociception/physiology , Nociceptors/metabolism , Osteoarthritis, Knee/physiopathology , Patch-Clamp Techniques , Posterior Horn Cells/metabolism
2.
Epidemiol Mikrobiol Imunol ; 64(4): 198-203, 2015 Oct.
Article in Czech | MEDLINE | ID: mdl-26795223

ABSTRACT

The pathogenesis of hepatitis C virus (HCV) infection is regulated by the host immunity and several metabolic factors affecting liver metabolism, including oxidative stress, insulin resistance, and hepatic steatosis. Both innate and adaptive immunity play an important role in HCV infection. Cytotoxic lymphocytes have a crucial role in viral eradication or viral persistence. Major cause of viral persistence during HCV infection could be the development of a weak antiviral immune response to the viral antigens, with corresponding inability to eradicate infected cells.


Subject(s)
Hepacivirus/immunology , Hepatitis C/immunology , Animals , Hepacivirus/genetics , Hepacivirus/pathogenicity , Hepatitis C/virology , Humans , T-Lymphocytes, Cytotoxic/immunology
3.
Thromb Haemost ; 112(6): 1230-43, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25104417

ABSTRACT

Early diagnosis of severe infectious diseases is essential for timely implementation of lifesaving therapies. In a search for novel biomarkers in sepsis diagnosis we focused on polymorphonuclear neutrophils (PMNs). Notably, PMNs have their protein cargo readily stored in granules and following systemic stimulation, an immediate increase of neutrophil-borne proteins can be observed into the circulation of sepsis patients. We applied a combination of mass spectrometry (MS) based approaches, LC-MS/MS and selected reaction monitoring (SRM), to characterise and quantify the neutrophil proteome in healthy or disease conditions. With this approach we identified a neutrophil-derived protein abundance pattern in blood plasma consisting of 20 proteins that can be used as a protein signature for severe infectious diseases. Our results also show that SRM is highly sensitive, specific, and reproducible and, thus, a promising technology to study a complex, dynamic and multifactorial disease such as sepsis.


Subject(s)
Blood Proteins/metabolism , Chromatography, Liquid , Neutrophils/metabolism , Proteomics/methods , Sepsis/blood , Tandem Mass Spectrometry , Biomarkers/metabolism , Case-Control Studies , Disease Progression , Humans , Neutrophils/immunology , Neutrophils/microbiology , Predictive Value of Tests , Sepsis/diagnosis , Sepsis/immunology , Sepsis/microbiology , Severity of Illness Index
4.
J Physiol Sci ; 59(2): 97-103, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19340549

ABSTRACT

This study was designed in order to consider whether the release of neuronally derived nitric oxide (NO) in the lumbosacral spinal cord during ischemia/reperfusion is region-specific and whether changes in Ca(2+)-dependent NO synthase (cNOS) activity paralell with functional outcome. The cNOS activity was measured in the spinal cord regions after 13-, 15- and 17-min ischemia alone and that followed by 24 h of reperfusion. In addition, the Tarlov's criteria were applied to define the neurological consequences of ischemia/reperfusion in experimental animals. Based on the results, it is evident that only the 17-min ischemia alone was quite sufficient to cause changes in cNOS activity, however, without alterations in functional outcomes. On the other hand, the ischemic episodes followed by reperfusion caused dynamic, region-specific alterations in cNOS activity and consequently led to deterioration of motor function of hindlimbs in affected animals. Our results indicate that the motoneurons in the ventral horns respond more sensitively to ischemia/reperfusion than do neurons localized in the other spinal cord regions and that changes in cNOS activity may also influence the axonal conductance in the white matter and account for the impairment of motoneuronal activity in affected animals.


Subject(s)
Nitric Oxide Synthase/metabolism , Reperfusion Injury/enzymology , Spinal Cord/enzymology , Animals , Anterior Horn Cells/enzymology , Anterior Horn Cells/physiopathology , Calcium/metabolism , Male , Models, Animal , Rabbits , Reperfusion Injury/physiopathology , Spinal Cord/physiopathology , Time Factors
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