Fibroblast growth factor 21 (FGF21), a metabolic hormone with pleiotropic effects, is beneficial for various cardiac disorders. However, FGF21's role in heart failure with preserved ejection fraction (HFpEF) remains unclear. Here, we show that elevated circulating FGF21 levels are negatively associated with cardiac diastolic function in patients with HFpEF. Global or adipose FGF21 deficiency exacerbates cardiac diastolic dysfunction and damage in high-fat diet (HFD) plus N[w]-nitro-L-arginine methyl ester (L-NAME)-induced HFpEF mice, whereas these effects are notably reversed by FGF21 replenishment. Mechanistically, FGF21 enhances the production of adiponectin (APN), which in turn indirectly acts on cardiomyocytes, or FGF21 directly targets cardiomyocytes, to negatively regulate pyruvate dehydrogenase kinase 4 (PDK4) production by activating PI3K/AKT signals, then promoting mitochondrial bioenergetics. Additionally, APN deletion strikingly abrogates FGF21's protective effects against HFpEF, while genetic PDK4 inactivation markedly mitigates HFpEF in mice. Thus, FGF21 protects against HFpEF via fine-tuning the multiorgan crosstalk among the adipose, liver, and heart.

• MeSH
• adiponektin * metabolismus   genetika   MeSH
• dieta s vysokým obsahem tuků * škodlivé účinky   MeSH
• energetický metabolismus * účinky léků   MeSH
• fibroblastové růstové faktory * metabolismus   genetika   MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• kardiomyocyty * metabolismus   účinky léků   MeSH
• lidé MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• PDH-kinasa * metabolismus   genetika   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• signální transdukce MeSH
• srdeční mitochondrie * metabolismus   účinky léků   MeSH
• srdeční selhání * metabolismus   prevence a kontrola   genetika   MeSH
• tepový objem účinky léků   MeSH
• tuková tkáň metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: ANCA-associated vasculitis (AAV) is a rare, life-threatening disease which may result in serious pulmonary and kidney damage. Cyclophosphamide or rituximab and high-dose glucocorticoids significantly improved patient outcomes, but at the expense of severe complications. Moreover, many patients still relapse and bear a significant burden of both disease- and treatment-related complications. Alternative complement pathway and C5a receptor signaling were demonstrated to play an important role in AAV pathogenesis. Avacopan is selective C5a receptor inhibitor successfully tested in renal AAV as glucocorticoid-sparing agent. AREAS COVERED: Pharmacokinetic/pharmacodynamic properties, clinical efficacy and safety of avacopan, available clinical trials and real-world experience with avacopan. EXPERT OPINION: In the phase 3 trial avacopan was shown to be non-inferior at six and superior at 12 months compared to high-dose glucocorticoids and either cyclophosphamide or rituximab in patients with active AAV. Treatment with avacopan was well tolerated and associated with improved quality of life. In patients with severe renal AAV, renal function improved more in avacopan-treated than in high-dose glucocorticoid-treated patients. Avacopan could thus replace high-dose glucocorticoids to avoid glucocorticoid-related toxicity and to improve long term renal outcome. As avacopan is CYP 3A4 inhibitor and substrate, drug-drug interactions must be considered during the treatment.

• MeSH
• ANCA-asociované vaskulitidy * farmakoterapie   MeSH
• aniliny MeSH
• cyklofosfamid aplikace a dávkování   škodlivé účinky   farmakologie   MeSH
• glukokortikoidy * aplikace a dávkování   farmakologie   škodlivé účinky   MeSH
• imunosupresiva aplikace a dávkování   škodlivé účinky   farmakologie   MeSH
• kombinovaná farmakoterapie MeSH
• kvalita života * MeSH
• kyseliny nipekotinové MeSH
• lidé MeSH
• receptor pro anafylatoxin C5a antagonisté a inhibitory   MeSH
• rituximab škodlivé účinky   aplikace a dávkování   farmakologie   MeSH
• stupeň závažnosti nemoci MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• srovnávací studie MeSH

BACKGROUND: Prostate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles IL6ST-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. However, the molecular programs mediated by IL6ST/STAT3 in prostate cancer are poorly understood. METHODS: To investigate the role of IL6ST signaling, we constitutively activated IL6ST signaling in the prostate epithelium of a Pten-deficient prostate cancer mouse model in vivo and examined IL6ST expression in large cohorts of prostate cancer patients. We complemented these data with in-depth transcriptomic and multiplex histopathological analyses. RESULTS: Genetic cell-autonomous activation of the IL6ST receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growth in vivo. Mechanistically, genetic activation of IL6ST signaling mediates senescence via the STAT3/ARF/p53 axis and recruitment of cytotoxic T-cells, ultimately impeding tumor progression. In prostate cancer patients, high IL6ST mRNA expression levels correlate with better recurrence-free survival, increased senescence signals and a transition from an immune-cold to an immune-hot tumor. CONCLUSIONS: Our findings demonstrate a context-dependent role of IL6ST/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development by inducing senescence and immune cell attraction. We challenge the prevailing concept of blocking IL6ST/STAT3 signaling as a functional prostate cancer treatment and instead propose cell-autonomous IL6ST activation as a novel therapeutic strategy.

• MeSH
• inhibitor p16 cyklin-dependentní kinasy metabolismus   genetika   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádorové mikroprostředí * MeSH
• nádorový supresorový protein p53 * metabolismus   genetika   MeSH
• nádory prostaty * patologie   metabolismus   genetika   MeSH
• regulace genové exprese u nádorů MeSH
• signální transdukce * MeSH
• stárnutí buněk * MeSH
• transkripční faktor STAT3 * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Rituximab (RTX) plus chemotherapy (R-CHOP) applied as a first-line therapy for lymphoma leads to a relapse in approximately 40% of the patients. Therefore, novel approaches to treat aggressive lymphomas are being intensively investigated. Several RTX-resistant (RR) cell lines have been established as surrogate models to study resistance to R-CHOP. Our study reveals that RR cells are characterized by a major downregulation of CD37, a molecule currently explored as a target for immunotherapy. Using CD20 knockout (KO) cell lines, we demonstrate that CD20 and CD37 form a complex, and hypothesize that the presence of CD20 stabilizes CD37 in the cell membrane. Consequently, we observe a diminished cytotoxicity of anti-CD37 monoclonal antibody (mAb) in complement-dependent cytotoxicity in both RR and CD20 KO cells that can be partially restored upon lysosome inhibition. On the other hand, the internalization rate of anti-CD37 mAb in CD20 KO cells is increased when compared to controls, suggesting unhampered efficacy of antibody drug conjugates (ADCs). Importantly, even a major downregulation in CD37 levels does not hamper the efficacy of CD37-directed chimeric antigen receptor (CAR) T cells. In summary, we present here a novel mechanism of CD37 regulation with further implications for the use of anti-CD37 immunotherapies.

• MeSH
• antigeny CD20 * imunologie   metabolismus   genetika   MeSH
• antigeny nádorové imunologie   genetika   MeSH
• B-buněčný lymfom * imunologie   terapie   genetika   farmakoterapie   MeSH
• chemorezistence účinky léků   MeSH
• chimerické antigenní receptory imunologie   genetika   metabolismus   MeSH
• cyklofosfamid farmakologie   terapeutické užití   MeSH
• doxorubicin farmakologie   aplikace a dávkování   MeSH
• imunoterapie * metody   MeSH
• lidé MeSH
• monoklonální protilátky farmakologie   terapeutické užití   MeSH
• nádorové buněčné linie MeSH
• protokoly protinádorové kombinované chemoterapie farmakologie   terapeutické užití   MeSH
• regulace genové exprese u nádorů MeSH
• rituximab * farmakologie   terapeutické užití   MeSH
• tetraspaniny * genetika   metabolismus   MeSH
• vinkristin farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The fungal pathogen Candida albicans is linked to chronic brain diseases such as Alzheimer's disease (AD), but the molecular basis of brain anti-Candida immunity remains unknown. We show that C. albicans enters the mouse brain from the blood and induces two neuroimmune sensing mechanisms involving secreted aspartic proteinases (Saps) and candidalysin. Saps disrupt tight junction proteins of the blood-brain barrier (BBB) to permit fungal brain invasion. Saps also hydrolyze amyloid precursor protein (APP) into amyloid β (Aβ)-like peptides that bind to Toll-like receptor 4 (TLR4) and promote fungal killing in vitro while candidalysin engages the integrin CD11b (Mac-1) on microglia. Recognition of Aβ-like peptides and candidalysin promotes fungal clearance from the brain, and disruption of candidalysin recognition through CD11b markedly prolongs C. albicans cerebral mycosis. Thus, C. albicans is cleared from the brain through innate immune mechanisms involving Saps, Aβ, candidalysin, and CD11b.

• MeSH
• Alzheimerova nemoc metabolismus   mikrobiologie   MeSH
• amyloidní beta-protein metabolismus   MeSH
• antigeny CD11b * metabolismus   MeSH
• Candida albicans metabolismus   MeSH
• fungální proteiny metabolismus   MeSH
• mikroglie * metabolismus   mikrobiologie   MeSH
• mykózy * genetika   metabolismus   MeSH
• myši MeSH
• toll-like receptor 4 * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

Komplementový systém je klíčovou složkou vrozené imunity. Skládá se z 50 plazmatických a membránových proteinů, které tvoří tři odlišné, ale překrývající se dráhy aktivace, stejně jako společnou terminální lytickou kaskádu a síť regulátorů a receptorů. Poruchy komplementu se mohou podílet na vzniku imunodeficiencí, autoimunit, malignit, infekčních onemocnění a na chorobách spojených s dysregulací komplementu. Striktní dodržování pravidel preanalytické fáze vyšetření je zásadní pro laboratorní diagnostiku. Pro komplexní posouzení funkce a zapojení komplementu do imunopatologických procesů, musíme testovat celou paletu vyšetření (od funkčních testů, vyšetření jednotlivých složek komplementu, až po genetickou analýzu).

The complement system is a key component of innate immunity. It consists of 50 plasma and membrane proteins that form three distinct but overlapping pathways of activation, as well as a common terminal lytic cascade and a network of regulators and receptors. Complement disorders may contribute to immunodeficiencies, autoimmunity, malignancies, infectious diseases, and diseases associated with complement dysregulation. Strict adherence to the rules of the preanalytical phase of the examination is essential for laboratory diagnosis. To comprehensively assess the function and involvement of complement in immunopathological processes, we need to perform a whole range of investigations (from functional tests, examination of individual complement components, to genetic analysis).

• MeSH
• atypický hemolyticko-uremický syndrom diagnóza   genetika   MeSH
• komplement MeSH
• lidé MeSH
• test hemolytické aktivity komplementu * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

The pertussis agent Bordetella pertussis produces a number of virulence factors, of which the filamentous hemagglutinin (FhaB) plays a role in B. pertussis adhesion to epithelial and phagocytic cells. Moreover, FhaB was recently found to play a crucial role in nasal cavity infection and B. pertussis transmission to new hosts. The 367 kDa FhaB protein translocates through an FhaC pore to the outer bacterial surface and is eventually processed to a ~220 kDa N-terminal FHA fragment by the SphB1 protease. A fraction of the mature FHA then remains associated with bacterial cell surface, while most of FHA is shed into the bacterial environment. Previously reported indirect evidence suggested that FHA, or its precursor FhaB, may bind the β2 integrin CD11b/CD18 of human macrophages. Therefore, we assessed FHA binding to various cells producing or lacking the integrin and show that purified mature FHA does not bind CD11b/CD18. Further results then revealed that the adhesion of B. pertussis to cells does not involve an interaction between the bacterial surface-associated FhaB and/or mature FHA and the β2 integrin CD11b/CD18. In contrast, FHA binding was strongly inhibited at micromolar concentrations of heparin, corroborating that the cell binding of FHA is ruled by the interaction of its heparin-binding domain with sulfated glycosaminoglycans on the cell surface.

• MeSH
• antigeny CD18 MeSH
• bakteriální adheze MeSH
• bakteriální adheziny metabolismus   MeSH
• Bordetella pertussis * metabolismus   MeSH
• faktory virulence rodu Bordetella MeSH
• glykosaminoglykany MeSH
• hemaglutininy metabolismus   MeSH
• heparin MeSH
• integriny MeSH
• lidé MeSH
• makrofágový antigen 1 MeSH
• pertuse * MeSH
• proteasy MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: Recent development of novel antidiabetic drugs with proven cardiovascular (CV) and renal benefit and positive effect on body weight enable to take a more complex approach toward the management of type 2 diabetes mellitus (T2DM). Fixed-ratio combinations of insulin-GLP-1 receptor agonist (FRC) utilize complementary mechanisms of action of their individual components and address multiple pathologies linked with T2DM at the same time. AREAS COVERED: There are currently three FRCs on the market: iGlarLixi (glargine and lixisenatide in 2 different formulations) and IDegLira (degludec and liraglutide). We provide an up-to-date review on the rationale for the use of FRCs and their current position in the management of T2DM. We discuss the available evidence from randomized controlled trials, post hoc analyses, indirect comparative studies and real-world data on their effect on glycemic control, risk of hypoglycemia, body weight, CV safety, and their safety profile. EXPERT OPINION: FRCs represent an efficacious option for treatment intensification from basal insulin or even the first insulin-based therapy in T2DM. Their excellent glucose-lowering efficacy is complemented with lower risk of hypoglycemia in comparison to basal insulin, neutral effect on body weight and the lower risk of gastrointestinal adverse effects in comparison to GLP-1 receptor agonists.

• MeSH
• diabetes mellitus 2. typu * farmakoterapie   MeSH
• fixní kombinace léků MeSH
• glykovaný hemoglobin MeSH
• hypoglykemie * chemicky indukované   MeSH
• hypoglykemika škodlivé účinky   MeSH
• inzulin glargin terapeutické užití   MeSH
• krevní glukóza MeSH
• lidé MeSH
• receptor pro glukagonu podobný peptid 1 agonisté   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Saccharides form one of the major constituents of biological macromolecules in living organisms. Many biological processes including protein folding, stability, immune response and receptor activation are regulated by glycosylation. In this work, we optimized a capillary electrophoresis method with capacitively coupled contactless conductivity detection for the separation of eight monosaccharides commonly found in glycoproteins, namely D-glucose, D-galactose, D-mannose, N-acetyl-D-glucosamine, N-acetyl-D-galactosamine, D-fucose, N-acetylneuraminic acid, and D-xylose. A highly alkaline solution of 50 mM sodium hydroxide, 22.5 mM disodium phosphate, and 0.2 mM CTAB (pH 12.4) was used as a background electrolyte in a 10 μm id capillary. To achieve baseline separation of all analytes, a counter-directional pressure of -270 kPa was applied during the separation. The limits of detection of our method were below 7 μg/ml (i.e., 1.5 pg or 1 mg/g protein) and the limits of quantification were below 22 μg/ml (i.e., 5 pg or 3 mg/g protein). As a proof of concept of our methodology, we performed an analysis of monosaccharides released from fetuin glycoprotein by acid hydrolysis. The results show that, when combined with an appropriate pre-concentration technique, the developed method can be used as a monosaccharide profiling tool in glycoproteomics and complement the routinely used LC-MS/MS analysis.

• MeSH
• acetylgalaktosamin MeSH
• acetylglukosamin MeSH
• cetrimonium MeSH
• chromatografie kapalinová MeSH
• elektroforéza kapilární metody   MeSH
• elektrolyty chemie   MeSH
• fetuiny MeSH
• fosfáty MeSH
• fukosa MeSH
• galaktosa MeSH
• glukosa MeSH
• glykoproteiny chemie   MeSH
• hydroxid sodný MeSH
• kyselina N-acetylneuraminová * MeSH
• mannosa MeSH
• monosacharidy * analýza   MeSH
• tandemová hmotnostní spektrometrie MeSH
• xylosa MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• alkylační látky farmakologie   terapeutické užití   MeSH
• autoprotilátky analýza   imunologie   MeSH
• biopsie metody   MeSH
• diuretika farmakologie   terapeutické užití   MeSH
• imunosupresivní léčba metody   MeSH
• inhibitory ACE farmakologie   terapeutické užití   MeSH
• inhibitory kalcineurinu farmakologie   terapeutické užití   MeSH
• lidé MeSH
• membranoproliferativní glomerulonefritida * diagnóza   farmakoterapie   MeSH
• nefrotický syndrom etiologie   MeSH
• paraneoplastické syndromy MeSH
• receptory pro fosfolipasy A2 analýza   imunologie   MeSH
• rituximab farmakologie   terapeutické užití   MeSH
• statiny farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH