Overactivation of the innate immune system together with the impaired downstream pathway of type I interferon-responding genes is a hallmark of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc). To date, limited data on the cross-disease innate gene signature exists among those diseases. We compared therefore an innate gene signature of Toll-like receptors (TLRs), seven key members of the interleukin (IL)1/IL1R family, and CXCL8/IL8 in peripheral blood mononuclear cells from well-defined patients with active stages of RA (n = 36, DAS28 ≥ 3.2), SLE (n = 28, SLEDAI > 6), and SSc (n = 22, revised EUSTAR index > 2.25). Emerging diversity and abundance of the innate signature in RA patients were detected: RA was characterized by the upregulation of TLR3, TLR5, IL1RAP/IL1R3, IL18R1, and SIGIRR/IL1R8 when compared to SSc (Pcorr < 0.02) and of TLR2, TLR5, and SIGIRR/IL1R8 when compared to SLE (Pcorr < 0.02). Applying the association rule analysis, six rules (combinations and expression of genes describing disease) were identified for RA (most frequently included high TLR3 and/or IL1RAP/IL1R3) and three rules for SLE (low IL1RN and IL18R1) and SSc (low TLR5 and IL18R1). This first cross-disease study identified emerging heterogeneity in the innate signature of RA patients with many upregulated innate genes compared to that of SLE and SSc.
- MeSH
- dospělí MeSH
- interleukin-1 genetika metabolismus MeSH
- interleukin-8 genetika metabolismus MeSH
- leukocyty mononukleární metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- přirozená imunita genetika MeSH
- receptory interleukinu-1 - typ I genetika metabolismus MeSH
- revmatoidní artritida krev genetika imunologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- systémová sklerodermie krev genetika imunologie MeSH
- systémový lupus erythematodes krev genetika imunologie MeSH
- toll-like receptory genetika metabolismus MeSH
- transkriptom MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
OBJECTIVES: Hedgehog signalling plays a critical role during the pathogenesis of fibrosis in systemic sclerosis (SSc). Besides canonical hedgehog signalling with smoothened (SMO)-dependent activation of GLI transcription factors, GLI can be activated independently of classical hedgehog ligands and receptors (so-called non-canonical pathways). Here, we aimed to evaluate the role of non-canonical hedgehog signalling in SSc and to test the efficacy of direct GLI inhibitors that target simultaneously canonical and non-canonical hedgehog pathways. METHODS: The GLI inhibitor GANT-61 was used to inhibit canonical as well as non-canonical hedgehog signalling, while the SMO inhibitor vismodegib was used to selectively target canonical hedgehog signalling. Furthermore, GLI2 was selectively depleted in fibroblasts using the Cre-LoxP system. The effects of pharmacological or genetic of GLI2 on transforming growth factor-β (TGF-β) signalling were analysed in cultured fibroblasts, in bleomycin-induced pulmonary fibrosis and in mice with overexpression of a constitutively active TGF-β receptor I. RESULTS: TGF-β upregulated GLI2 in a Smad3-dependent manner and induced nuclear accumulation and DNA binding of GLI2. Fibroblast-specific knockout of GLI2 protected mice from TBR(act)-induced fibrosis. Combined targeting of canonical and non-canonical hedgehog signalling with direct GLI inhibitors exerted more potent antifibrotic effects than selective targeting of canonical hedgehog signalling with SMO inhibitors in experimental dermal and pulmonary fibrosis. CONCLUSIONS: Our data demonstrate that hedgehog pathways and TGF-β signalling both converge to GLI2 and that GLI2 integrates those signalling to promote tissue fibrosis. These findings may have translational implications as non-selective inhibitors of GLI2 are in clinical use and selective molecules are currently in development.
- MeSH
- anilidy farmakologie MeSH
- dospělí MeSH
- fibroblasty účinky léků metabolismus MeSH
- fibróza MeSH
- genový knockout MeSH
- inhibitor aktivátoru plazminogenu 1 genetika MeSH
- kolagen typu I genetika MeSH
- kultivované buňky MeSH
- kůže účinky léků patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- messenger RNA metabolismus MeSH
- mladý dospělý MeSH
- myši knockoutované MeSH
- myši transgenní MeSH
- myši MeSH
- plicní fibróza chemicky indukované metabolismus MeSH
- protein Smad3 metabolismus MeSH
- protein-serin-threoninkinasy antagonisté a inhibitory genetika MeSH
- proteiny hedgehog metabolismus MeSH
- pteridiny farmakologie MeSH
- pyridiny farmakologie MeSH
- pyrimidiny farmakologie MeSH
- receptor Smoothened antagonisté a inhibitory MeSH
- receptory transformujícího růstového faktoru beta antagonisté a inhibitory genetika MeSH
- rekombinantní proteiny farmakologie MeSH
- růstový faktor pojivové tkáně genetika MeSH
- senioři MeSH
- signální transdukce účinky léků MeSH
- systémová sklerodermie genetika metabolismus MeSH
- transformující růstový faktor beta metabolismus farmakologie MeSH
- transkripční faktory Krüppel-like antagonisté a inhibitory genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- myši MeSH
- senioři MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: The phase 2b Riociguat Safety and Efficacy in Patients with Diffuse Cutaneous Systemic Sclerosis (RISE-SSc) trial investigated riociguat versus placebo in early diffuse cutaneous systemic sclerosis. The long-term extension evaluated safety and exploratory treatment effects for an additional year. METHODS: Patients were enrolled to RISE-SSc between Jan 15, 2015, and Dec 8, 2016. Those who completed the 52-week, randomised, parallel-group, placebo-controlled, double-blind phase were eligible for the long-term extension. Patients originally assigned to riociguat continued therapy (riociguat-riociguat group). Those originally assigned to placebo were switched to riociguat (placebo-riociguat group), adjusted up to 2·5 mg three times daily in a 10-week, double-blind dose-adjustment phase, followed by an open-label phase. Statistical analyses were descriptive. Safety including adverse events and serious adverse events was assessed in the long-term safety analysis set (all patients randomly assigned and treated with study medication in the double-blind phase who continued study medication in the long-term extension). The RISE-SSc trial is registered with ClinicalTrials.gov, NCT02283762. FINDINGS: In total, 87 (72%) of 121 patients in the main RISE-SSc study entered the long-term extension (riociguat-riociguat, n=42; placebo-riociguat, n=45). 65 (75%) of 87 patients were women, 22 (25%) were men, and 62 (71%) were White. Overall, 82 (94%) of 87 patients in the long-term extension had an adverse event; most (66 [76%] of 87) were of mild to moderate severity, with no increase in pulmonary-related serious adverse events in patients with interstitial lung disease. INTERPRETATION: No new safety signals were observed with long-term riociguat in patients with early diffuse cutaneous systemic sclerosis. Study limitations include the absence of a comparator group in this open-label extension study. FUNDING: Bayer and Merck Sharp & Dohme.
- MeSH
- difuzní sklerodermie * farmakoterapie MeSH
- lidé MeSH
- pacienti MeSH
- pyrazoly škodlivé účinky MeSH
- pyrimidiny * MeSH
- výzkumný projekt MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- randomizované kontrolované studie MeSH
OBJECTIVES: Riociguat is approved for pulmonary arterial hypertension and has antiproliferative, anti-inflammatory and antifibrotic effects in animal models of tissue fibrosis. We evaluated the efficacy and safety of riociguat in patients with early diffuse cutaneous systemic sclerosis (dcSSc) at high risk of skin fibrosis progression. METHODS: In this randomised, double-blind, placebo-controlled, phase IIb trial, adults with dcSSc of <18 months' duration and a modified Rodnan skin score (mRSS) 10-22 units received riociguat 0.5 mg to 2.5 mg orally three times daily (n=60) or placebo (n=61). The primary endpoint was change in mRSS from baseline to week 52. RESULTS: At week 52, change from baseline in mRSS units was -2.09±5.66 (n=57) with riociguat and -0.77±8.24 (n=52) with placebo (difference of least squares means -2.34 (95% CI -4.99 to 0.30; p=0.08)). In patients with interstitial lung disease, forced vital capacity declined by 2.7% with riociguat and 7.6% with placebo. At week 14, average Raynaud's condition score had improved ≥50% in 19 (41.3%)/46 patients with riociguat and 13 (26.0%)/50 patients with placebo. Safety assessments showed no new signals with riociguat and no treatment-related deaths. CONCLUSIONS: Riociguat did not significantly benefit mRSS versus placebo at the predefined p<0.05. Secondary and exploratory analyses showed potential efficacy signals that should be tested in further trials. Riociguat was well tolerated.
- MeSH
- aktivátory enzymů aplikace a dávkování MeSH
- difuzní sklerodermie farmakoterapie patologie MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- hodnocení rizik MeSH
- imunohistochemie MeSH
- internacionalita MeSH
- jehlová biopsie MeSH
- lidé středního věku MeSH
- lidé MeSH
- následné studie MeSH
- neúspěšná terapie MeSH
- pyrazoly aplikace a dávkování MeSH
- pyrimidiny aplikace a dávkování MeSH
- respirační funkční testy MeSH
- rozvrh dávkování léků MeSH
- stupeň závažnosti nemoci MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: High-velocity concentric actions can be negatively impacted by cumulative fatigue during plyometric training. Reducing vertical ground reaction forces (GRF) upon landing could decrease eccentric demands, potentially minimizing fatigue, maintaining concentric performance, and benefiting concentric training adaptations. Therefore, this study examined the effect of intentionally higher and lower landing vertical GRF on the ability to sustain concentric jumping performance. METHODS: Twenty men (25.2±3.5 years) performed 30 maximal effort jumps over a 50 cm hurdle (high-landing GRF) and onto a 50 cm box (low-landing GRF), on two separate occasions in a counter-balanced order. Jumps were measured using two force platforms (one for takeoff and one for landing) and a linear position transducer. The 30 jumps were divided into 5 groups of 6 repetitions, and the mean value for each group was analyzed. RESULTS: There was no significant condition × repetition group interaction for any parameters, indicating that the greater landing GRF during hurdle jumps did not negatively affect concentric jump performance throughout the 30 jumps. Concentric velocities and jump height were significantly greater during box jumps compared to hurdle jumps. CONCLUSIONS: Thirty maximal-effort jumps did not cause fatigue-related decrease of performance, independent of jump type (i.e., the magnitude of landing GRF). Although, reduced vertical GRF upon landing appears to have a neutral-to-positive effect on concentric jumping performance. Therefore, reducing landing GRF, such as by using BJs, could acutely augment jumping performance and help to reduce cumulative training load.
- MeSH
- biomechanika MeSH
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- plyometrická cvičení * MeSH
- sportovní výkon * fyziologie MeSH
- svalová únava fyziologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
7 sv.
- MeSH
- diagnostické zobrazování MeSH
- spektrální analýza MeSH
- Publikační typ
- periodika MeSH
- Konspekt
- Technika všeobecně
- NLK Obory
- chemie, klinická chemie
- technika
- fyzika, biofyzika
