Danikopan je selektivní inhibitor faktoru D komplementu, který působí přes alternativní cestu aktivace komplementu. Blokádou alternativní dráhy komplementu danikopan inhibuje extravaskulární hemolýzu (EVH). Účinnost a bezpečnost danikopanu u dospělých pacientů s paroxyzmální noční hemoglobinurií (PNH) s klinicky významnou EVH byly hodnoceny v multicentrické, randomizované, dvojitě zaslepené, placebem kontrolované studii fáze 3 ALXN2040-PNH-301. Danikopan přidaný k ravulizumabu nebo ekulizumabu prokázal superioritu v primárním cílovém parametru zvýšení hladiny hemoglobinu oproti placebu. Danikopan také dosáhl statisticky významného zlepšení ve srovnání s placebem u všech 4 sekundárních cílových parametrů, které byly podíl pacientů se zvýšením hladiny hemoglobinu o ≥ 20 g/l, počet pacientů bez potřeby transfuze, změna ve skóre únavy podle FACIT a změna absolutního počtu retikulocytů. Kombinace léčby danikopanem s inhibitory terminální fáze komplentu C5 stabilizuje i primární intravaskulární hemolýzu danou základním onemocněním PNH. Danikopan je indikován jako přídatná léčba k ravulizumabu nebo ekulizumabu k léčbě dospělých pacientů s paroxyzmální noční hemoglobinurií, kteří mají reziduální hemolytickou anémii.

Danicopan is a selective inhibitor of complement factor D that acts through the alternative pathway of complement activation. By blocking the alternative pathway of complement, danikopan inhibits extravascular hemolysis (EVH). The efficacy and safety of danikopan in adult PNH patients with clinically significant EVH were evaluated in a multicenter, randomized, double-blind, placebo-controlled, phase 3 study ALXN2040-PNH-301. Danicopan added to ravulizumab or eculizumab demonstrated superiority over placebo in the primary endpoint of increase in hemoglobin levels. Danicopan also achieved statistically significant improvements compared to placebo in all 4 secondary endpoints, which were the proportion of patients with an increase in hemoglobin levels of ≥ 20 g/L, the number of patients without a transfusion, the change in FACIT fatigue score, and the change in absolute reticulocyte count. The combination of danicopan treatment with C5 terminal phase inhibitors also stabilizes primary intravascular hemolysis due to the underlying PNH disease. Danicopan is indicated as an add-on therapy to ravulizumab or eculizumab for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria who have residual hemolytic anemia.

• Keywords
• danikopan,
• MeSH
• Complement Factor D antagonists & inhibitors   pharmacology   therapeutic use   MeSH
• Humans MeSH
• Hemoglobinuria, Paroxysmal * drug therapy   MeSH
• Randomized Controlled Trials as Topic MeSH
• Check Tag
• Humans MeSH

Zvýšený oxidační stres při cévních onemocněních stimuluje sekreci adipokinů z adipocytů. Řada klinických studií prokázala, že hodnoty adipsinu v plazmě poměrně spolehlivě predikují vznik ischemických příhod. Zvýšené hodnoty adipsinu těsně souvisejí s úmrtím z jakýchkoli příčin a s morbiditou. Adipsin je tak novým biomarkerem při sledování rozvoje aterosklerózy. Cílem tohoto přehledu bylo zdůraznit souvislost mezi adipsinem a kardiovaskulárními onemocněními a přínos použití adipsinu v léčbě těchto onemocnění.

Increased vascular oxidative stress stimulates the secretion of adipokines from adipocytes. Many clinical studies have demonstrated that plasma adipsin levels are successful in predicting ischemic events. Increased adipsin levels are closely related to all-cause death and morbidity. Therefore, adipsin may be a new biomarker for atherosclerosis. In this review, we aimed to emphasize the association of adipsin with cardiovascular diseases (CVDs) and its beneficial role in the therapeutic field of CVDs.

• Keywords
• Adipsin, Atherosclerosis, Cardiovascular disease, Adipsin, Ateroskleróza, Kardiovaskulární onemocnění,
• MeSH
• Atherosclerosis diagnosis   physiopathology   MeSH
• Biomarkers analysis   MeSH
• Cardiovascular Diseases * diagnosis   physiopathology   MeSH
• Complement Factor D * analysis   physiology   adverse effects   MeSH
• Humans MeSH
• Oxidative Stress MeSH
• Prognosis MeSH
• Check Tag
• Humans MeSH
• Publication type
• Review MeSH

Peripheral insulin resistance is associated with decreasing adiponectin and increasing leptin plasma levels, and also with cognitive decline. The effects of adipokines on brain function have been published from both animal and human studies. In particular, the influence of leptin and adiponectin on the development of Alzheimer's disease (AD) has been extensively investigated. However, the association between adipsin and AD is as yet unknown. In 37 patients with AD and 65 controls that followed the same study protocol, we tested whether adiponectin, leptin, and adipsin could be used as biomarkers in the early stages of AD. In contrast with conclusions of cognition studies in insulin resistant states, our study found a correlation of impaired neuropsychological performance with increasing adiponectin and decreasing leptin in AD patients. Nevertheless, no significant differences between patients and controls were found. AD women had significantly increased adipsin compared to controls, and there was a positive correlation of adipsin with age and disease duration. Although adipokines do not appear to be suitable biomarkers for early AD diagnosis, they certainly play a role in the pathogenesis of AD. Further studies will be needed to explain the cause of the adipokine "breaking point" that leads to the pathogenesis of overt AD.

• MeSH
• Adiponectin blood   MeSH
• Alzheimer Disease blood   pathology   MeSH
• Biomarkers blood   MeSH
• Complement Factor D analysis   MeSH
• Leptin blood   MeSH
• Middle Aged MeSH
• Humans MeSH
• Case-Control Studies MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Acquired or genetic abnormalities of the complement alternative pathway are the primary cause of C3glomerulopathy(C3G) but may occur in immune-complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) as well. Less is known about the presence and role of C4nephritic factor(C4NeF) which may stabilize the classical pathway C3-convertase. Our aim was to examine the presence of C4NeF and its connection with clinical features and with other pathogenic factors. RESULTS: One hunfe IC-MPGN/C3G patients were enrolled in the study. C4NeF activity was determined by hemolytic assay utilizing sensitized sheep erythrocytes. Seventeen patients were positive for C4NeF with lower prevalence of renal impairment and lower C4d level, and higher C3 nephritic factor (C3NeF) prevalence at time of diagnosis compared to C4NeF negative patients. Patients positive for both C3NeF and C4NeF had the lowest C3 levels and highest terminal pathway activation. End-stage renal disease did not develop in any of the C4NeF positive patients during follow-up period. Positivity to other complement autoantibodies (anti-C1q, anti-C3) was also linked to the presence of nephritic factors. Unsupervised, data-driven cluster analysis identified a group of patients with high prevalence of multiple complement autoantibodies, including C4NeF. CONCLUSIONS: In conclusion, C4NeF may be a possible cause of complement dysregulation in approximately 10-15% of IC-MPGN/C3G patients.

• MeSH
• Autoantibodies immunology   metabolism   MeSH
• Adult MeSH
• Complement C3 Nephritic Factor metabolism   MeSH
• Complement System Proteins metabolism   MeSH
• Humans MeSH
• Glomerulonephritis, Membranoproliferative immunology   metabolism   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Kidney Diseases immunology   metabolism   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

• MeSH
• Allergy and Immunology MeSH
• Immune System MeSH
• Publication type
• Textbook MeSH

• Conspectus
• Patologie. Klinická medicína
• Učební osnovy. Vyučovací předměty. Učebnice
• NML Fields
• alergologie a imunologie

BACKGROUND: Complement is thought to play a role in immunoglobulin A nephropathy (IgAN), though the activating mechanisms are unknown. This study focused on the gene expression of CD46 and CD55, two key molecules for regulating C3 convertase activity of lectin and alternative complement pathways at a cellular level. METHODS: The transcriptional expression in peripheral white blood cells (WBCs) of CD46 and CD55 was investigated in 157 patients enrolled by the Validation of the Oxford Classification of IgAN group, looking for correlations with clinical and pathology features and estimated glomerular filtration rate (eGFR) modifications from renal biopsy to sampling. Patients had a previous median follow-up of 6.4 (interquartile range 2.8-10.7) years and were divided into progressors and non-progressors according to the median value of their velocity of loss of renal function per year (-0.41 mL/min/1.73 m2/year). RESULTS: CD46 and CD55 messenger RNA (mRNA) expression in WBCs was not correlated with eGFR values or proteinuria at sampling. CD46 mRNA was significantly correlated with eGFR decline rate as a continuous outcome variable (P = 0.014). A significant difference was found in CD46 gene expression between progressors and non-progressors (P = 0.013). CD46 and CD55 mRNA levels were significantly correlated (P < 0.01), although no difference between progressors and non-progressors was found for CD55 mRNA values. The prediction of progression was increased when CD46 and CD55 mRNA expressions were added to clinical data at renal biopsy (eGFR, proteinuria and mean arterial blood pressure) and Oxford MEST-C (mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis, presence of any crescents) score. CONCLUSIONS: Patients with progressive IgAN showed lower expression of mRNA encoding for the complement inhibitory protein CD46, which may implicate a defective regulation of C3 convertase with uncontrolled complement activation.

• MeSH
• Membrane Cofactor Protein blood   genetics   MeSH
• Biomarkers blood   MeSH
• Adult MeSH
• Glomerulonephritis, IGA blood   diagnosis   genetics   MeSH
• Complement Inactivating Agents blood   MeSH
• Middle Aged MeSH
• Humans MeSH
• RNA, Messenger blood   genetics   MeSH
• Prognosis MeSH
• Disease Progression MeSH
• Gene Expression Regulation MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Serine peptidases are involved in many physiological processes including digestion, haemostasis and complement cascade. Parasites regulate activities of host serine peptidases to their own benefit, employing various inhibitors, many of which belong to the Kunitz-type protein family. In this study, we confirmed the presence of potential anticoagulants in protein extracts of the haematophagous monogenean Eudiplozoon nipponicum which parasitizes the common carp. We then focused on a Kunitz protein (EnKT1) discovered in the E. nipponicum transcriptome, which structurally resembles textilinin-1, an antihemorrhagic snake venom factor from Pseudonaja textilis. The protein was recombinantly expressed, purified and biochemically characterised. The recombinant EnKT1 did inhibit in vitro activity of Factor Xa of the coagulation cascade, but exhibited a higher activity against plasmin and plasma kallikrein, which participate in fibrinolysis, production of kinins, and complement activation. Anti-coagulation properties of EnKT1 based on the inhibition of Factor Xa were confirmed by thromboelastography, but no effect on fibrinolysis was observed. Moreover, we discovered that EnKT1 significantly impairs the function of fish complement, possibly by inhibiting plasmin or Factor Xa which can act as a C3 and C5 convertase. We localised Enkt1 transcripts and protein within haematin digestive cells of the parasite by RNA in situ hybridisation and immunohistochemistry, respectively. Based on these results, we suggest that the secretory Kunitz protein of E. nipponicum has a dual function. In particular, it impairs both haemostasis and complement activation in vitro, and thus might facilitate digestion of a host's blood and protect a parasite's gastrodermis from damage by the complement. This study presents, to our knowledge, the first characterisation of a Kunitz protein from monogeneans and the first example of a parasite Kunitz inhibitor that impairs the function of the complement.

• MeSH
• Antifibrinolytic Agents chemistry   immunology   MeSH
• Anticoagulants chemistry   immunology   MeSH
• Factor Xa immunology   MeSH
• Hemostasis * MeSH
• Trematode Infections blood   immunology   parasitology   veterinary   MeSH
• Enzyme Inhibitors chemistry   immunology   MeSH
• Factor Xa Inhibitors chemistry   immunology   MeSH
• Host-Parasite Interactions MeSH
• Carps blood   immunology   parasitology   MeSH
• Complement System Proteins immunology   MeSH
• Fish Diseases blood   immunology   parasitology   MeSH
• Fibrinolysin immunology   MeSH
• Plasma Kallikrein antagonists & inhibitors   immunology   MeSH
• Helminth Proteins chemistry   genetics   immunology   MeSH
• Amino Acid Sequence MeSH
• Sequence Alignment MeSH
• Trematoda chemistry   genetics   immunology   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Ticks possess components of a primordial complement system that presumably play a role in the interaction of the tick immune system with tick-borne pathogens and affect their transmission. Here we characterized a novel complement component, tagged as IrC2/Bf, from the hard tick Ixodes ricinus, the principal vector of Lyme disease in Europe. IrC2/Bf is a multi-domain molecule composed of 5-7 CCP modules, varied by alternative splicing, followed by a von Willebrand factor A domain and a C-terminal trypsin-like domain. The primary structure and molecular architecture of IrC2/Bf displays the closest homology to the C3-complement component convertases described in horseshoe crabs. The irc2/bf gene is mainly expressed in the tick fat body associated with the trachea and, as determined by western blotting, the protein is present in low amounts in tick hemolymph. Expression of irc2/bf mRNA was significantly up-regulated in response to the intra-hemocoelic injection of the yeast Candida albicans and all tested Borrelia sp. strains (B. burgdorferi NE5264, B. burgdorferi CB26, B. garinii MSLB, B. afzelii CB43), but was not affected by injection of model Gram-negative and Gram-positive bacteria or the aseptic injection control. In-line with these results, RNAi-mediated silencing of irc2/bf inhibited phagocytosis of B. afzelii and C. albicans but not the other bacteria. Tissue expression profiles, specific responses to microbial challenges, and patterns of phagocytic phenotypes upon RNAi silencing observed for IrC2/Bf match well with the previously reported characteristics of I. ricinus C3-related molecule 1 (IrC3-1). Therefore we presume that IrC2/Bf functions as a convertase in the same complement activation pathway protecting ticks against yeast and Borrelia infection.

• MeSH
• Complement Activation MeSH
• Borrelia burgdorferi immunology   MeSH
• Candida albicans immunology   MeSH
• Phagocytosis MeSH
• Hemocytes immunology   microbiology   MeSH
• Insect Proteins genetics   metabolism   MeSH
• Disease Vectors MeSH
• Host-Pathogen Interactions MeSH
• Candidiasis immunology   MeSH
• Ixodes immunology   MeSH
• Complement C3 genetics   metabolism   MeSH
• Humans MeSH
• Lyme Disease immunology   MeSH
• RNA, Small Interfering genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Alzheimerova nemoc je progresivní neurodegenerativní onemocnění charakterizované ukládáním β-amyloidu a hyperfosforylací τ-proteinu v postiženém mozku. Jedná se o multifaktoriální onemocnění, na jehož patologii se podílejí jak faktory genetické, tak faktory vnějšího prostředí. Kromě genetického pozadí Alzheimerovy nemoci se stále častěji diskutuje o pozadí biochemickém. Mezi jedny z biochemických markerů, které mohou ovlivňovat Alzheimerovu nemoc, patří adipokiny. Adipokiny jsou bílkoviny produkované tukovou tkání, které po vyplavení do krevního řečiště ovlivňují řadu procesů. Vliv adipokinů na rozvoj Alzheimerovy nemoci je patrný, avšak ne zcela jednoznačný. Tento přehled popisuje roli vybraných adipokinů při vzniku a rozvoji Alzheimerovy nemoci.

Alzheimer's disease is a progressive neurodegenerative disorder characterized by the deposition of β-amyloid and hyperphosphorylation of τ-protein in a brain. The pathology of this multifactorial disease is influenced by genetic as well as environmental factors. In addition to the genetic background of Alzheimer's disease, there are increasingly discussed biochemical background. Among some of the biochemical markers that can affect the Alzheimer's disease are adipokines. Adipokines are proteins secreted by adipose tissue, which after flooding to the bloodstream affect a variety of processes. The influence of adipokines in development of Alzheimer's disease is evident, however not entirely clear. This review describes the role of selected adipokines in the creation and development of Alzheimer's disease.

• MeSH
• Adipokines * physiology   MeSH
• Adiponectin physiology   MeSH
• Alzheimer Disease * etiology   metabolism   pathology   MeSH
• Energy Metabolism physiology   MeSH
• Complement Factor D physiology   MeSH
• Leptin physiology   MeSH
• Humans MeSH
• Mitochondria physiology   metabolism   MeSH
• Nicotinamide Phosphoribosyltransferase physiology   MeSH
• Resistin physiology   MeSH
• Adipose Tissue metabolism   MeSH
• Inflammation metabolism   MeSH
• Check Tag
• Humans MeSH

• MeSH
• Immunity MeSH
• Immune System physiology   physiopathology   MeSH
• Immunotherapy MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• alergologie a imunologie
• biologie
• fyziologie
• NML Publication type
• kolektivní monografie