Search results for "ACTIVATOR"

2021

Orthodontic treatment to correct dental malocclusions leads to the formation of pressure zones in the periodontal ligament resulting in a sterile inflammatory reaction, which is mediated by periodontal ligament fibroblasts (PDLF). Leptin levels are elevated in obesity and chronic inflammatory responses. In view of the increasing number of orthodontic patients with these conditions, insights into effects on orthodontic treatment are of distinct clinical relevance. A possible influence of leptin on the expression profile of PDLF during simulated orthodontic mechanical strain, however, has not yet been investigated. In this study, PDLF were exposed to mechanical strain with or without differen…

Measurement of Bradykinin Formation and Degradation in Blood Plasma: Relevance for Acquired Angioedema Associated With Angiotensin Converting Enzyme …

2020

Bradykinin (BK)-mediated angioedema (AE) states are rare acquired or hereditary conditions involving localized edema of the subcutaneous and submucosal tissues. Citrated plasma from healthy volunteers or patients with hereditary angioedema (HAE) with normal level of C1-inhibitor (C1-INH) was used to investigate pathways of BK formation and breakdown relevant to AE physiopathology. The half-life of BK (100 nM) added to normal plasma was 34 s, a value that was increased ~12-fold when the angiotensin converting enzyme (ACE) inhibitor enalaprilat (130 nM) was added (enzyme immunoassay measurements). The BK half-life was similarly increased ~5-fold following 2 daily oral doses of enalapril malea…

Deficiency of plasminogen activator inhibitor 2 in plasma of patients with hereditary angioedema with normal C1 inhibitor levels

2016

Background Hereditary angioedema with normal C1 inhibitor levels (HAE-N) is associated with a Factor XII mutation in 30% of subjects; however, the role of this mutation in the pathogenesis of angioedema is unclear. Objective We sought evidence of abnormalities in the pathways of bradykinin formation and bradykinin degradation in the plasma of patients with HAE-N both with and without the mutation. Methods Bradykinin was added to plasma, and its rate of degradation was measured by using ELISA. Plasma autoactivation was assessed by using a chromogenic assay of kallikrein formation. Plasminogen activator inhibitors (PAIs) 1 and 2 were also measured by means of ELISA. Results PAI-1 levels varie…

The MID1 protein is a central player during development and in disease.

2015

Loss-of-function mutations in the MID1 gene cause a rare monogenic disorder, Opitz BBB/G syndrome (OS), which is characterized by malformations of the ventral midline. The MID1 gene encodes the MID1 protein, which assembles a large microtubule-associated protein complex. Intensive research over the past several years has shed light on the function of the MID1 protein as a ubiquitin ligase and regulator of mTOR signalling and translational activator. As a central player in the cell MID1 has been implicated in the pathogenesis of various other disorders in addition to OS including cancer and neurodegenerative diseases. Influencing the activity of the MID1 protein complex is a promising new st…

SMAC mimetics promote NIK-dependent inhibition of CD4 + T H 17 cell differentiation

2019

Second mitochondria-derived activator of caspase (SMAC) mimetics (SMs) are selective antagonists of the inhibitor of apoptosis proteins (IAPs), which activate noncanonical NF-κB signaling and promote tumor cell death. Through gene expression analysis, we found that treatment of CD4+ T cells with SMs during T helper 17 (TH17) cell differentiation disrupted the balance between two antagonistic transcription factor modules. Moreover, proteomics analysis revealed that SMs altered the abundance of proteins associated with cell cycle, mitochondrial activity, and the balance between canonical and noncanonical NF-κB signaling. Whereas SMs inhibited interleukin-17 (IL-17) production and ameliorated …

Coronavirus Disease 2019–Associated Coagulopathy

2021

Patients with the severe form of coronavirus disease 2019 (COVID-19) have been frequently found to suffer from both arterial and venous thrombotic events due to the perpetuation of a hypercoagulable state. This phenomenon, termed COVID-19-associated coagulopathy (CC), is now considered a major component of the pathophysiology of this novel infectious disease, leading to widespread thrombosis. While at first, the vascular insults may be limited to the pulmonary microvasculature, as the disease progresses, systemic involvement occurs, culminating in distant organ thrombosis and multi-organ dysfunction syndrome. In this review article, we discuss recent insights into the pathophysiologic mecha…

Systematic Analysis of Combined Thrombolysis Using Ultrasound and Different Fibrinolytic Drugs in an in Vitro Clot Model of Intracerebral Hemorrhage.

2021

Adequate removal of blood clots by minimally invasive surgery seems to correlate with a better clinical outcome in patients with intracerebral hemorrhages (ICHs). Moreover, neurotoxic effects of recombinant tissue plasminogen activator have been reported. The aim of this study was to improve fibrinolysis using an intra-clot ultrasound application with tenecteplase and urokinase in our established ICH clot model. One hundred thirty clots were produced from 25 or 50 mL of human blood, incubated for different periods and equipped with drainage, through which an ultrasound catheter was placed in 65 treatment clots for 1 h, randomly allocated into three groups: administration of ultrasound, admi…

The effect of the interferon-γ-inducible processing machinery on the generation of a naturally tumor-associated human cytotoxic T lymphocyte epitope …

2002

The human wild-type (wt) p53.264–272 peptide is a universal tumor antigen and recognized by HLA-A*0201 (A2.1)-restricted CTL. Generation of this epitope by constitutive 20S proteasomes is prevented by a p53 R to H hotspot mutation at the C-terminal flanking residue 273. We report on the impact of the interferon-γ (IFN-γ)-inducible proteasomal activator PA28 (11S regulator) and the immunoproteasome on the in vitro and cellular processing of wt and mutant (mut) p53 substrates. We found that production of the antigenic 264–272 peptide from wt p53 by constitutive as well as immunoproteasomes is accelerated and amplified by the PA28 activator. PA28 and (immuno)proteasomes were not capable to rec…

Coexpression of IL-6 and soluble IL-6R causes nodular regenerative hyperplasia and adenomas of the liver

1998

Studies with tumor necrosis factor p55 receptor- and interleukin-6 (IL-6)-deficient mice have shown that IL-6 is required for hepatocyte proliferation and reconstitution of the liver mass after partial hepatectomy. The biological activities of IL-6 are potentiated when this cytokine binds soluble forms of its specific receptor subunit (sIL-6R) and the resulting complex interacts with the transmembrane signaling chain gp130. We show here that double transgenic mice expressing high levels of both human IL-6 and sIL-6R under the control of liver-specific promoters spontaneously develop nodules of hepatocellular hyperplasia around periportal spaces and present signs of sustained hepatocyte prol…

Topical application of the Wnt/β-catenin activator methyl vanillate increases hair count and hair mass index in women with androgenetic alopecia

2016

Activation of the WNT/β-catenin pathway has emerged as a potential therapeutic target in androgenetic alopecia (AGA). Methyl vanillate (MV) - a safe plant-derived ingredient - has been recently shown to activate the WNT/β-catenin signaling. Objectives Two distinct substudies were conducted. First, we designed a 6-month, uncontrolled, open-label clinical study to investigate whether topically applied MV may increase hair count and hair mass index (HMI) in female AGA. Second, we conducted a molecular study on the effect of MV on WNT10B mRNA expression in scalp biopsies of women with AGA. A total of 20 Caucasian women (age range: 25-57 years) with AGA (Sinclair grade 1-2) were included. The re…