BACKGROUND: Currently, the diagnosis and treatment of neuroblastomas-the most frequent solid tumors in children-exploit the norepinephrine transporter (hNET) via radiolabeled norepinephrine analogs. We aim to develop a nanomedicine-based strategy towards precision therapy by targeting hNET cell-surface protein with hNET-derived homing peptides. RESULTS: The peptides (seq. GASNGINAYL and SLWERLAYGI) were shown to bind high-resolution homology models of hNET in silico. In particular, one unique binding site has marked the sequence and structural similarities of both peptides, while most of the contribution to the interaction was attributed to the electrostatic energy of Asn and Arg (< - 228 kJ/mol). The peptides were comprehensively characterized by computational and spectroscopic methods showing ~ 21% β-sheets/aggregation for GASNGINAYL and ~ 27% α-helix for SLWERLAYGI. After decorating 12-nm ferritin-based nanovehicles with cysteinated peptides, both peptides exhibited high potential for use in actively targeted neuroblastoma nanotherapy with exceptional in vitro biocompatibility and stability, showing minor yet distinct influences of the peptides on the global expression profiles. Upon binding to hNET with fast binding kinetics, GASNGINAYLC peptides enabled rapid endocytosis of ferritins into neuroblastoma cells, leading to apoptosis due to increased selective cytotoxicity of transported payload ellipticine. Peptide-coated nanovehicles significantly showed higher levels of early apoptosis after 6 h than non-coated nanovehicles (11% and 7.3%, respectively). Furthermore, targeting with the GASNGINAYLC peptide led to significantly higher degree of late apoptosis compared to the SLWERLAYGIC peptide (9.3% and 4.4%, respectively). These findings were supported by increased formation of reactive oxygen species, down-regulation of survivin and Bcl-2 and up-regulated p53. CONCLUSION: This novel homing nanovehicle employing GASNGINAYLC peptide was shown to induce rapid endocytosis of ellipticine-loaded ferritins into neuroblastoma cells in selective fashion and with successful payload. Future homing peptide development via lead optimization and functional analysis can pave the way towards efficient peptide-based active delivery of nanomedicines to neuroblastoma cells.

• Klíčová slova
• Ferritin, Homing peptide, Neuroblastoma, Norepinephrine transporter, Targeted therapy,
• MeSH
• antitumorózní látky chemie   farmakokinetika   farmakologie   MeSH
• endocytóza genetika   MeSH
• ferritin chemie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nanomedicína MeSH
• nanostruktury chemie   MeSH
• neuroblastom metabolismus   MeSH
• peptidy chemie   genetika   metabolismus   MeSH
• proteiny přenášející noradrenalin přes plazmatickou membránu * chemie   genetika   metabolismus   MeSH
• systémy cílené aplikace léků metody   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antitumorózní látky MeSH
• ferritin MeSH
• peptidy MeSH
• proteiny přenášející noradrenalin přes plazmatickou membránu * MeSH

Multiwall carbon nanotubes (MWCNTs) are among the frequently studied carbon materials, particularly because of their physical and chemical properties and high potential for application in materials chemistry, industry, and medicine. MWCNTs are very promising as transporters of bioactive molecules because of their π electrons and large surface area, which can be easily modified, mostly by the application of inorganic acids for the introduction of carboxylic moieties on the surface. In the present study, we designed an oxidised MWCNTs (oMWCNTs) transporter for the targeted delivery of doxorubicin (Dox). The modification of oMWCNTs with prostate-homing peptide (SMSIARL) promotes increased cytotoxicity for prostate cancer cells. Using advanced analytical techniques, we studied the loading efficiency, stability, and release kinetics of Dox from a oMWCNTs-Dox-Pep nanoconstruct. We show that pH strictly drives Dox release, and imitating the pH of intracellular acidic compartments, 60% of Dox is released from oMWCNTs-Dox-Pep, while in plasma conditions, only a 14% release of Dox was found during 24h. The nanoconstruct displayed no cytotoxicity in non-malignant prostate cells (PNT1A), while in metastatic prostate cancer cells (LNCaP), the cytotoxic effects were close to the cytotoxicity of free Dox. This indicates that peptide modification promotes interactions with malignant cells, resulting in efficient internalisation into the intracellular region. Overall, we show that oMWCNTs are exceptional platforms for simple and stable non-covalent modification with bioactive molecules.

• Klíčová slova
• Carbon nanomaterial, Drug delivery, Nanomedicine, Prostate-homing peptide,
• MeSH
• antibiotika antitumorózní chemie   MeSH
• doxorubicin chemie   MeSH
• kinetika MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nanotrubičky uhlíkové * MeSH
• prostata metabolismus   MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
• spektroskopie infračervená s Fourierovou transformací MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antibiotika antitumorózní MeSH
• doxorubicin MeSH
• nanotrubičky uhlíkové * MeSH

• MeSH
• antigeny povrchové * analýza   klasifikace   fyziologie   MeSH
• CD antigeny MeSH
• diferenciační antigeny klasifikace   MeSH
• histokompatibilita - antigeny třídy I MeSH
• integriny MeSH
• leukocyty imunologie   MeSH
• lidé MeSH
• membránové glykoproteiny imunologie   MeSH
• molekuly buněčné adheze MeSH
• receptory antigenů MeSH
• receptory buněčného povrchu MeSH
• receptory Fc MeSH
• receptory odpovědné za homing lymfocytů MeSH
• transportní proteiny MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antigeny povrchové * MeSH
• CD antigeny MeSH
• diferenciační antigeny MeSH
• histokompatibilita - antigeny třídy I MeSH
• integriny MeSH
• membránové glykoproteiny MeSH
• molekuly buněčné adheze MeSH
• receptory antigenů MeSH
• receptory buněčného povrchu MeSH
• receptory Fc MeSH
• receptory odpovědné za homing lymfocytů MeSH
• transportní proteiny MeSH

INTRODUCTION: Home parenteral nutrition (HPN) is the primary treatment modality for patients with chronic intestinal failure, one of the least common organ failures. This article provides a retrospective analysis of the data collected on HPN patients in the Czech Republic over the past 30 years. METHODS: National registry data were collected using a standardised online form based on the OASIS registry (Oley - A.S.P.E.N. Information System) across all centres providing HPN in the Czech Republic. Data collected prospectively from adult patients in the HPN program were analysed in the following categories: epidemiology, demographics, underlying syndrome, diagnosis, complications, and teduglutide therapy prevalence. RESULTS: The registry identified a total of 1,838 adult patient records, reflecting almost 1.5 million individual catheter days. The prevalence of HPN has risen considerably over the last few decades, currently reaching 5.5 per 100,000 population. The majority of patients have short bowel syndrome and GI obstruction, with cancer being the most prevalent underlying disease. Catheter-related bloodstream infections have been the most prevalent acute complication. However, the incidence in 2022 was only 0.15 per 1,000 catheter days. The study also observed an increase in the prevalence of patients on palliative HPN over the last decade. CONCLUSION: This study presents a thorough analysis of data from the Czech REgistr Domaci NUtricni Podpory (REDNUP) registry. It shows an increasing prevalence of HPN, namely, in the palliative patient group. The sharing of national data can improve understanding of this rare condition and facilitate the development of international guidelines.

• Klíčová slova
• Chronic intestinal failure, Epidemiology, Home parenteral nutrition, National registry,
• MeSH
• dospělí MeSH
• katétrové infekce epidemiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• parenterální výživa doma * statistika a číselné údaje   MeSH
• peptidy aplikace a dávkování   MeSH
• prevalence MeSH
• registrace * MeSH
• retrospektivní studie MeSH
• selhání střeva terapie   epidemiologie   MeSH
• senioři MeSH
• syndrom krátkého střeva terapie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika epidemiologie   MeSH
• Názvy látek
• peptidy MeSH
• teduglutide MeSH Prohlížeč

The proliposome-liposome method is based on the conversion of the initial proliposome preparation into a liposome dispersion by dilution with the aqueous phase. This technique is characterized by an extremely high entrapment efficiency and is suitable for the encapsulation of a wide range of drugs with different water and alcohol solubility. A description of a home-made stirred thermostated cell and its linkup with an FPLC system for a rapid and automated preparation of multilamellar liposomes under strictly controlled conditions (temperature, dilution rate, and schedule) is presented. The highly reproducible procedure yields multilamellar liposomes with a high encapsulation efficiency for various drugs. Carboxyfluorescein, as a model hydrophilic compound, was entrapped with an efficiency of 81 +/- 2%. The antibiotics neomycin and gentamycin were entrapped with efficiencies of 65 and 69%, respectively. Synthetic immunomodulators adamantylamide dipeptide, muramyl dipeptide, and beta-D-GlcNAc-norMurNAc-L-Abu-D-isoGln were entrapped with efficiencies of 87, 62, and 85%, respectively. The photosensitizer mesotetra-(parasulfophenyl)-porphin was entrapped with an efficiency of 65%. The cell has been designed for laboratory-scale preparation of liposomes (300-1000 mg of phospholipid per run) in a procedure taking less than 90 min. The method can be readily scaled up and linked with secondary processing methods, such as pressure extrusion through polycarbonate filters.

• MeSH
• adjuvancia imunologická aplikace a dávkování   chemická syntéza   MeSH
• antibakteriální látky aplikace a dávkování   MeSH
• fotosenzibilizující látky aplikace a dávkování   MeSH
• kontaminace léku MeSH
• liposomy chemická syntéza   MeSH
• nosiče léků chemická syntéza   MeSH
• peptidy aplikace a dávkování   chemická syntéza   MeSH
• teplota * MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• zmrazování MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adjuvancia imunologická MeSH
• antibakteriální látky MeSH
• fotosenzibilizující látky MeSH
• liposomy MeSH
• nosiče léků MeSH
• peptidy MeSH

AIMS: Residual beta cell function in type 1 diabetes (T1D) is associated with lower risk of complications. Autoantigen therapy with GAD-alum (Diamyd) given in 3 intralymphatic injections with oral vitamin D has shown promising results in persons with T1D carrying the human leukocyte antigen (HLA) DR3-DQ2 haplotype in the phase 2b trial DIAGNODE-2. We aimed to explore the efficacy of intralymphatic GAD-alum on blood glucose recorded by continuous glucose monitoring (CGM). METHODS: DIAGNODE-2 (NCT03345004) was a multicenter, randomized, placebo-controlled, double-blind trial of 109 recent-onset T1D patients aged 12 to 24 years with GAD65 antibodies and fasting C-peptide > 0.12 nmol/L, which randomized patients to 3 intralymphatic injections of 4 μg GAD-alum and oral vitamin D, or placebo. We report results for exploratory endpoints assessed by 14-day CGM at months 0, 6, and 15. Treatment arms were compared by mixed-effects models for repeated measures adjusting for baseline values. RESULTS: We included 98 patients with CGM recordings of sufficient quality (DR3-DQ2-positive patients: 27 GAD-alum-treated and 15 placebo-treated). In DR3-DQ2-positive patients, percent of time in range (TIR, 3.9-10 mmol/L) declined less between baseline and month 15 in GAD-alum-treated compared with placebo-treated patients (-5.1% and -16.7%, respectively; P = 0.0075), with reduced time > 13.9 mmol/L (P = 0.0036), and significant benefits on the glucose management indicator (P = 0.0025). No differences were detected for hypoglycemia. GAD-alum compared to placebo lowered the increase in glycemic variability (standard deviation) observed in both groups (P = 0.0219). Change in C-peptide was correlated with the change in TIR. CONCLUSIONS: Intralymphatic GAD-alum improves glycemic control in recently diagnosed T1D patients carrying HLA DR3-DQ2.

• Klíčová slova
• C-peptide, Diamyd, GAD-alum, GAD65, HLA DR3-DQ2, HbA1c, antigen-specific immune therapy, continuous glucose monitoring, type 1 diabetes,
• MeSH
• C-peptid MeSH
• diabetes mellitus 1. typu * MeSH
• dítě MeSH
• glutamát dekarboxyláza MeSH
• HLA-DR3 antigen MeSH
• kamencové sloučeniny MeSH
• krevní glukóza MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• regulace glykemie MeSH
• selfmonitoring glykemie MeSH
• vitamin D terapeutické užití   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• aluminum sulfate MeSH Prohlížeč
• C-peptid MeSH
• glutamát dekarboxyláza MeSH
• HLA-DR3 antigen MeSH
• kamencové sloučeniny MeSH
• krevní glukóza MeSH
• vitamin D MeSH

Suppressive function of regulatory T cells (Treg) is dependent on signaling of their antigen receptors triggered by cognate self, dietary, or microbial peptides presented on MHC II. However, it remains largely unknown whether distinct or shared repertoires of Treg TCRs are mobilized in response to different challenges in the same tissue or the same challenge in different tissues. Here we use a fixed TCRβ chain FoxP3-GFP mouse model to analyze conventional (eCD4) and regulatory (eTreg) effector TCRα repertoires in response to six distinct antigenic challenges to the lung and skin. This model shows highly 'digital' repertoire behavior with easy-to-track challenge-specific TCRα CDR3 clusters. For both eCD4 and eTreg subsets, we observe challenge-specific clonal expansions yielding homologous TCRα clusters within and across animals and exposure sites, which are also reflected in the draining lymph nodes but not systemically. Some CDR3 clusters are shared across cancer challenges, suggesting a response to common tumor-associated antigens. For most challenges, eCD4 and eTreg clonal response does not overlap. Such overlap is exclusively observed at the sites of certain tumor challenges, and not systematically, suggesting transient and local tumor-induced eCD4=>eTreg plasticity. This transition includes a dominant tumor-responding eCD4 CDR3 motif, as well as characteristic iNKT TCRα CDR3. In addition, we examine the homeostatic tissue residency of clonal eTreg populations by excluding the site of challenge from our analysis. We demonstrate that distinct CDR3 motifs are characteristic of eTreg cells residing in particular lymphatic tissues, regardless of the challenge. This observation reveals the tissue-resident, antigen-specific clonal Treg populations.

• Klíčová slova
• CD4+ T cells, TCR repertoire, antigenic specificity, homing, immunology, inflammation, lung challenges, mouse, treg,
• MeSH
• buněčné klony MeSH
• CD4-pozitivní T-lymfocyty * MeSH
• myši MeSH
• peptidy MeSH
• receptory antigenů T-buněk genetika   MeSH
• regulační T-lymfocyty * MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• peptidy MeSH
• receptory antigenů T-buněk MeSH

AIM: To evaluate the efficacy of a fixed-ratio combination of insulin glargine 100 U/mL plus lixisenatide (iGlarLixi) in people with type 2 diabetes (T2D) using derived time-in-range (dTIR). METHODS: Participant-level data from LixiLan-L, LixiLan-O and LixiLan-G were pooled and dTIR (70-180 mg/dL), derived time-above-range (> 180 mg/dL) and derived time-below-range (dTBR; < 70 mg/dL) were calculated from participant seven-point self-monitored blood glucose profiles. RESULTS: This pooled analysis included data from 2420 participants receiving iGlarLixi (n = 1093), iGlar (n = 836), Lixi (n = 234) or a glucagon-like peptide-1 receptor agonist (GLP-1 RA) (n = 257). Numerically greater improvements in least square (LS) means dTIR were seen from baseline to end of treatment (EOT) with iGlarLixi (25.7%) versus iGlar (15.8%), Lixi (11.7%) or GLP-1 RA (16.2%). At EOT, the mean (standard deviation) dTBR was 0.71% ± 3.4%, 0.61% ± 3.2%, 0.08% ± 1.0% and 0.0% ± 0.0% for iGlarLixi, iGlar, Lixi and GLP-1 RA, respectively. In a subgroup analysis, participants aged younger than 65 years (n = 1690) and 65 years or older (n = 713) showed numerically greater improvements in LS means dTIR from baseline to EOT with iGlarLixi versus iGlar, Lixi or GLP-1 RA. CONCLUSIONS: iGlarLixi achieved improvements in dTIR, with low dTBR values, providing further evidence to inform clinical outcomes with the use of iGlarLixi.

• Klíčová slova
• derived time‐in‐range, fixed‐ratio combination, iGlarLixi, real‐world data, type 2 diabetes,
• MeSH
• agonisté receptoru pro glukagonu podobný peptid 1 MeSH
• diabetes mellitus 2. typu * farmakoterapie   krev   MeSH
• dospělí MeSH
• fixní kombinace léků MeSH
• glykovaný hemoglobin analýza   metabolismus   účinky léků   MeSH
• hypoglykemika * terapeutické užití   MeSH
• inzulin glargin * terapeutické užití   MeSH
• krevní glukóza * účinky léků   metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• peptidy * terapeutické užití   aplikace a dávkování   MeSH
• randomizované kontrolované studie jako téma MeSH
• receptor pro glukagonu podobný peptid 2 MeSH
• selfmonitoring glykemie MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• agonisté receptoru pro glukagonu podobný peptid 1 MeSH
• fixní kombinace léků MeSH
• glykovaný hemoglobin MeSH
• hypoglykemika * MeSH
• inzulin glargin * MeSH
• krevní glukóza * MeSH
• lixisenatide MeSH Prohlížeč
• peptidy * MeSH
• receptor pro glukagonu podobný peptid 2 MeSH

In genetically predisposed individuals, ingestion of wheat gliadin provokes a T-cell-mediated enteropathy, celiac disease. Gliadin fragments were previously reported to induce phenotypic maturation and Th1 cytokine production by human dendritic cells (DCs) and to boost their capacity to stimulate allogeneic T cells. Here, we monitor the effects of gliadin on migratory capacities of DCs. Using transwell assays, we show that gliadin peptic digest stimulates migration of human DCs and their chemotactic responsiveness to the lymph node-homing chemokines CCL19 and CCL21. The gliadin-induced migration is accompanied by extensive alterations of the cytoskeletal organization, with dissolution of adhesion structures, podosomes, as well as up-regulation of the CC chemokine receptor (CCR) 7 on cell surface and induction of cyclooxygenase (COX)-2 enzyme that mediates prostaglandin E2 (PGE₂) production. Blocking experiments confirmed that gliadin-induced migration is independent of the TLR4 signalling. Moreover, we showed that the α-gliadin-derived 31-43 peptide is an active migration-inducing component of the digest. The migration promoted by gliadin fragments or the 31-43 peptide required activation of p38 mitogen-activated protein kinase (MAPK). As revealed using p38 MAPK inhibitor SB203580, this was responsible for DC cytoskeletal transition, CCR7 up-regulation and PGE₂ production in particular. Taken together, this study provides a new insight into pathogenic features of gliadin fragments by demonstrating their ability to promote DC migration, which is a prerequisite for efficient priming of naive T cells, contributing to celiac disease pathology.

• MeSH
• aktivace enzymů účinky léků   MeSH
• biologické modely MeSH
• chemokin CCL19 farmakologie   MeSH
• chemokin CCL21 farmakologie   MeSH
• chemotaxe účinky léků   MeSH
• cyklooxygenasa 2 metabolismus   MeSH
• cytoskelet účinky léků   metabolismus   MeSH
• dendritické buňky cytologie   účinky léků   enzymologie   MeSH
• dinoproston biosyntéza   MeSH
• gliadin farmakologie   MeSH
• lidé MeSH
• MAP kinasový signální systém účinky léků   MeSH
• mitogenem aktivované proteinkinasy p38 metabolismus   MeSH
• peptidové fragmenty farmakologie   MeSH
• receptory CCR7 metabolismus   MeSH
• upregulace účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CCR7 protein, human MeSH Prohlížeč
• chemokin CCL19 MeSH
• chemokin CCL21 MeSH
• cyklooxygenasa 2 MeSH
• dinoproston MeSH
• gliadin MeSH
• mitogenem aktivované proteinkinasy p38 MeSH
• peptidové fragmenty MeSH
• PTGS2 protein, human MeSH Prohlížeč
• receptory CCR7 MeSH

Minimization of drug side effects is a hallmark of advanced targeted therapy. Herein we describe the synthesis of polysaccharide-based nanocapsules prepared from furcellaran and chitosan via layer-by-layer deposition using electrostatic interaction. Using doxorubicin as a model drug, prepared nanocapsules showed excellent drug loading properties and release influence by pH and stability. Targeted delivery of doxorubicin was achieved by nanocapsule surface modification using homing peptide (seq SMSIARLC). The synthesized nanocapsules possess excellent compatibility to eukaryotic organisms. In the case of nonmalignant cells (PNT1A and HEK-293), toxicity tests revealed the absences of DNA fragmentation, apoptosis, necrosis, and also disruption of erythrocyte membranes. In contrast, results from treatment of malignant cell lines (MDA-MB-231 and PC3) indicate good anticancer effects of synthesized bionanomaterial. Internalization studies revealed the nanocapsule's ability to enter the malignant cell lines by endocytosis and triggering the apoptosis. The occurrence of apoptosis is mostly connected to the presence of ROS and inability of DNA damage reparation. Additionally, the obtained results strongly indicate that peptide modification increases the speed of nanocapsule internalization into malignant cell lines while simultaneously nonmalignant cell lines are untouched by nanocapsules highlighting the strong selectivity of the peptide.

• MeSH
• algináty chemie   MeSH
• antigeny CD31 metabolismus   MeSH
• chitosan chemie   MeSH
• doxorubicin aplikace a dávkování   farmakokinetika   MeSH
• HEK293 buňky MeSH
• hemolýza účinky léků   MeSH
• koncentrace vodíkových iontů MeSH
• léky s prodlouženým účinkem * MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nanokapsle aplikace a dávkování   chemie   toxicita   MeSH
• peptidy chemie   metabolismus   MeSH
• polyelektrolyty chemie   MeSH
• rostlinné gumy chemie   MeSH
• systémy cílené aplikace léků metody   MeSH
• testy toxicity MeSH
• uvolňování léčiv MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• algináty MeSH
• antigeny CD31 MeSH
• chitosan MeSH
• doxorubicin MeSH
• furcellaran MeSH Prohlížeč
• léky s prodlouženým účinkem * MeSH
• nanokapsle MeSH
• peptidy MeSH
• polyelektrolyty MeSH
• rostlinné gumy MeSH