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
• Adiponectin * metabolism   genetics   MeSH
• Diet, High-Fat * adverse effects   MeSH
• Energy Metabolism * drug effects   MeSH
• Fibroblast Growth Factors * metabolism   genetics   MeSH
• Phosphatidylinositol 3-Kinases metabolism   MeSH
• Myocytes, Cardiac * metabolism   drug effects   MeSH
• Humans MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase * metabolism   genetics   MeSH
• Proto-Oncogene Proteins c-akt metabolism   MeSH
• Signal Transduction MeSH
• Mitochondria, Heart * metabolism   drug effects   MeSH
• Heart Failure * metabolism   prevention & control   genetics   MeSH
• Stroke Volume drug effects   MeSH
• Adipose Tissue metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article 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
• Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis * drug therapy   MeSH
• Aniline Compounds MeSH
• Cyclophosphamide administration & dosage   adverse effects   pharmacology   MeSH
• Glucocorticoids * administration & dosage   pharmacology   adverse effects   MeSH
• Immunosuppressive Agents administration & dosage   adverse effects   pharmacology   MeSH
• Drug Therapy, Combination MeSH
• Quality of Life * MeSH
• Nipecotic Acids MeSH
• Humans MeSH
• Receptor, Anaphylatoxin C5a antagonists & inhibitors   MeSH
• Rituximab adverse effects   administration & dosage   pharmacology   MeSH
• Severity of Illness Index MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Comparative Study 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
• Cyclin-Dependent Kinase Inhibitor p16 metabolism   genetics   MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Tumor Microenvironment * MeSH
• Tumor Suppressor Protein p53 * metabolism   genetics   MeSH
• Prostatic Neoplasms * pathology   metabolism   genetics   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Signal Transduction * MeSH
• Cellular Senescence * MeSH
• STAT3 Transcription Factor * metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Hereditární angioedém je autosomálně dominantně děděné onemocnění, které je charakterizováno opakujícími se atakami potenciálně život ohrožujících nesvědivých otoků v dermis a v submukóze. Recidivující zvracení s rizikem dehydratace a minerálního rozvratu může být prvním projevem v dětském věku. Léčbu lze rozdělit na léčbu akutních atak a na profylaxi: krátkodobou (před invazivním výkonem) či dlouhodobou (s cílem dosažení plné kontroly nad onemocněním s normalizací kvality života nemocných). K dlouhodobé profylaxi lze v České republice použít přípravky lanadelumab, berotralstat a plazmatický koncentrát Cl-inhibitoru.

Hereditary angioedema is an autosomal dominantly inherited disease characterized by recurrent attacks of potentially life-threatening, non-itching swellings in the dermis and submucosa. Recurrent vomiting with the risk of dehydration and mineral breakdown may be the first manifestation in childhood. Treatment can be divided into the treatment of acute attacks and prophylaxis: short-term (before invasive procedures) or long-term (with the aim of achieving full control over the disease and normalizing the quality of life of patients). The following preparations can be used for long-term prophylaxis in the Czech Republic currently: lanadelumab, berotralstat and plasma Cl-inhibitor concentrate.

• Keywords
• lanadelumab, icatibant,
• MeSH
• Bradykinin B2 Receptor Antagonists therapeutic use   MeSH
• Bradykinin analogs & derivatives   MeSH
• Child MeSH
• Double-Blind Method MeSH
• Angioedemas, Hereditary * diagnosis   drug therapy   pathology   MeSH
• Antibodies, Monoclonal, Humanized administration & dosage   therapeutic use   MeSH
• Complement C1 Inhibitor Protein therapeutic use   MeSH
• Kallikreins antagonists & inhibitors   MeSH
• Humans MeSH
• Multicenter Studies as Topic MeSH
• Randomized Controlled Trials as Topic MeSH
• Drugs, Investigational MeSH
• Vomiting etiology   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Case Reports 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
• Antigens, CD20 * immunology   metabolism   genetics   MeSH
• Antigens, Neoplasm immunology   genetics   MeSH
• Lymphoma, B-Cell * immunology   therapy   genetics   drug therapy   MeSH
• Drug Resistance, Neoplasm drug effects   MeSH
• Receptors, Chimeric Antigen immunology   genetics   metabolism   MeSH
• Cyclophosphamide pharmacology   therapeutic use   MeSH
• Doxorubicin pharmacology   administration & dosage   MeSH
• Immunotherapy * methods   MeSH
• Humans MeSH
• Antibodies, Monoclonal pharmacology   therapeutic use   MeSH
• Cell Line, Tumor MeSH
• Antineoplastic Combined Chemotherapy Protocols pharmacology   therapeutic use   MeSH
• Gene Expression Regulation, Neoplastic MeSH
• Rituximab * pharmacology   therapeutic use   MeSH
• Tetraspanins * genetics   metabolism   MeSH
• Vincristine pharmacology   therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article 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
• Alzheimer Disease metabolism   microbiology   MeSH
• Amyloid beta-Peptides metabolism   MeSH
• CD11b Antigen * metabolism   MeSH
• Candida albicans metabolism   MeSH
• Fungal Proteins metabolism   MeSH
• Microglia * metabolism   microbiology   MeSH
• Mycoses * genetics   metabolism   MeSH
• Mice MeSH
• Toll-Like Receptor 4 * metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't 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
• Atypical Hemolytic Uremic Syndrome diagnosis   genetics   MeSH
• Complement System Proteins MeSH
• Humans MeSH
• Complement Hemolytic Activity Assay * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review 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
• CD18 Antigens MeSH
• Bacterial Adhesion MeSH
• Adhesins, Bacterial metabolism   MeSH
• Bordetella pertussis * metabolism   MeSH
• Virulence Factors, Bordetella MeSH
• Glycosaminoglycans MeSH
• Hemagglutinins metabolism   MeSH
• Heparin MeSH
• Integrins MeSH
• Humans MeSH
• Macrophage-1 Antigen MeSH
• Whooping Cough * MeSH
• Peptide Hydrolases MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article 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, Type 2 * drug therapy   MeSH
• Drug Combinations MeSH
• Glycated Hemoglobin MeSH
• Hypoglycemia * chemically induced   MeSH
• Hypoglycemic Agents adverse effects   MeSH
• Insulin Glargine therapeutic use   MeSH
• Blood Glucose MeSH
• Humans MeSH
• Glucagon-Like Peptide-1 Receptor agonists   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article 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
• Acetylgalactosamine MeSH
• Acetylglucosamine MeSH
• Cetrimonium MeSH
• Chromatography, Liquid MeSH
• Electrophoresis, Capillary methods   MeSH
• Electrolytes chemistry   MeSH
• Fetuins MeSH
• Phosphates MeSH
• Fucose MeSH
• Galactose MeSH
• Glucose MeSH
• Glycoproteins chemistry   MeSH
• Sodium Hydroxide MeSH
• N-Acetylneuraminic Acid * MeSH
• Mannose MeSH
• Monosaccharides * analysis   MeSH
• Tandem Mass Spectrometry MeSH
• Xylose MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH