To elucidate the pathogenetic mechanism of renal parenchymal injury in autosomal dominant polycystic kidney disease (ADPKD) patients, typically characterized by renal cystic changes paralleled by interstitial inflammation and gradual fibrotic changes, the role of selected inflammatory mediators was evaluated in a group of ADPKD patients with normal glomerular filtration rate. The plasma concentrations of IL-6, IL-8, ICAM-1 and VCAM-1 (which may reflect systemic response to inflammation/infection) were increased in the ADPKD patient group. Coupled with decreased urinary excretion of the IL-1 receptor antagonist (which exerts an anti-inflammatory role), these results suggest that even in overt infection free status, the proinflammatory system is more activated and anti-inflammatory defence system weakened in ADPKD subjects. Our data support the current view that cytokines are candidate contributors to pathogenesis of ADPKD.

• MeSH
• cévní buněčněadhezivní molekula-1 krev   MeSH
• cytokiny krev   MeSH
• dospělí MeSH
• interleukin-1 krev   MeSH
• interleukin-6 krev   MeSH
• interleukin-8 krev   MeSH
• lidé MeSH
• mezibuněčná adhezivní molekula-1 krev   MeSH
• polycystické ledviny autozomálně dominantní krev   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cévní buněčněadhezivní molekula-1 MeSH
• cytokiny MeSH
• interleukin-1 MeSH
• interleukin-6 MeSH
• interleukin-8 MeSH
• mezibuněčná adhezivní molekula-1 MeSH

BackgroundThe ischemia-reperfusion injury (IRI) is unavoidable in vascular surgery. Damage to the microcirculation and endothelial glycocalyx might set up a shock with loss of circulatory coherence and organ failure. Sulodexide may help to protect endothelial glycocalyx and alleviate the ischemia-reperfusion injury.MethodsTwenty female piglets underwent surgery with a 30-min-long suprarenal aortic clamp, followed by two hours of reperfusion. Ten piglets received sulodexide before the clamp, and 10 received normal saline. Blood and urine samples were taken at baseline and in 20-min intervals until the 120th minute to analyze the serum syndecan-1, E-selectin, and thrombomodulin. Albumin and glycosaminoglycans were examined in the urine. The kidney biopsies before and after the protocol were examined by light microscopy with hematoxylin-eosin staining. The sublingual microcirculation was recorded by side-stream dark field imaging at the time as blood and urine.ResultsBased on the 2-way ANOVA testing, there was no statistically significant difference in the parameters of sublingual microcirculation. Serum markers of endothelial cell activation and damage (E-selectin and thrombomodulin) did not show any statistically significant difference either. Syndecan-1, a marker of glycocalyx damage, showed statistically significantly higher values based on the 2-way ANOVA testing (p < 0.0001) with the highest difference in the 80th minute: 7.8 (3.9-44) ng/mL in the control group and 1.8 (0.67-2.8) ng/mL in the sulodexide group. In the urine, the albuminuria was higher in the control group, although not statistically significant. Glycosaminoglycans were statistically significantly higher in the sulodexide group based on the mixed-effect analysis due to the intervention itself. Histological analysis of the renal biopsies showed necrosis in both groups after reperfusion.ConclusionAdministering sulodexide significantly reduced the level of endothelial markers of IRI. The study results support further research into using preemptive administration of sulodexide to modulate IRI in clinical medicine.

• Klíčová slova
• endothelial glycocalyx, ischemia-reperfusion, microcirculation, sulodexide, syndecan-1,
• MeSH
• E-selektin krev   MeSH
• glykokalyx MeSH
• glykosaminoglykany * farmakologie   terapeutické užití   MeSH
• ledviny patologie   krevní zásobení   MeSH
• mikrocirkulace účinky léků   MeSH
• modely nemocí na zvířatech MeSH
• prasata MeSH
• reperfuzní poškození * prevence a kontrola   MeSH
• syndekan-1 krev   MeSH
• trombomodulin krev   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• E-selektin MeSH
• glucuronyl glucosamine glycan sulfate MeSH Prohlížeč
• glykosaminoglykany * MeSH
• syndekan-1 MeSH
• trombomodulin MeSH

Objectives of the study were to investigate impact of ischemic preconditioning (Ipre) and sulforaphane (SFN) and combination of them on nuclear factor 2 erythroid related factor 2 (Nrf2) gene and its dependent genes, heme oxygenase-1 (HO1) and NADPH-quinone oxidoreductase1 (NQO-1) and inflammatory cytokines TNF-alpha, IL1beta, and intercellular adhesion molecule-1 (ICAM1) and caspase-3 in renal ischemia/reperfusion (I/R) injury. Ninety male Sprague Dawely rats were classified into 5 groups (each consists of 18 rats): sham, control, Ipre, sulforaphane and Sulfo+Ipre. Each group was subdivided into 3 subgroups each containing 6 rats according to time of harvesting kidney and taking blood samples; 24 h, 48 h, and 7 days subgroups. Renal functions including serum creatinine, BUN were measured at basal conditions and by the end of experiment. Expression of Nrf2, HO-1, NQO-1, TNF-alpha, IL-1beta, and ICAM-1 was measured by real time PCR in kidney tissues by the end of experiment. Also, immunohistochemical localization of caspase-3 and chemical assay of malondialdehyde (MDA), GSH and SOD activity were measured in kidney tissues. Both Ipre and SFN improved kidney functions, enhanced the expression of Nrf2, HO-1, and NQO-1, attenuated the expression of inflammatory (TNF-alpha, IL-1, and ICAM-1) and apoptotic (caspase-3) markers. However, the effect of sulforaphane was more powerful than Ipre. Also, a combination of them caused more improvement in antioxidant genes expression and more attenuation in inflammatory genes but not caspase-3 than each one did separately. Sulforaphane showed more powerful effect in renoprotection against I/R injury than Ipre as well as there might be a synergism between them at the molecular but not at the function level.

• MeSH
• akutní poškození ledvin diagnóza   imunologie   terapie   MeSH
• cytokiny imunologie   MeSH
• faktor 2 související s NF-E2 imunologie   MeSH
• isothiokyanatany aplikace a dávkování   MeSH
• kombinovaná terapie MeSH
• krysa rodu Rattus MeSH
• oxidační stres účinky léků   imunologie   MeSH
• potkani Sprague-Dawley MeSH
• přivykání k ischémii metody   MeSH
• reperfuzní poškození diagnóza   imunologie   terapie   MeSH
• sulfoxidy MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• cytokiny MeSH
• faktor 2 související s NF-E2 MeSH
• isothiokyanatany MeSH
• Nfe2l2 protein, rat MeSH Prohlížeč
• sulforaphane MeSH Prohlížeč
• sulfoxidy MeSH

M2 macrophages expressing CD163 are known to suppress immune responses but have been also found in biopsies of patients with chronic kidney allograft injury associated with interstitial fibrosis. The aim of our study was to evaluate the expression of CD163 in blood monocytes, precursors of tissue macrophages, in kidney allograft recipients with uncomplicated outcome (n=94) compared with those developing acute rejection (n=44). Blood samples were collected before the transplantation and at 1 week, 1 month and 1 year. The expression of CD163 increased during the first week after the transplantation not only in classical (CD14+CD16-) but also in intermediate (CD14+CD16+) and nonclassical (CD14lowCD16+) monocytes in all patients regardless of their rejection status. In patients developing acute rejection, higher pre-transplant expression of CD163 on blood monocytes was found. In vitro experiments confirmed strong induction of membrane CD163 on monocytes together with CD206 (an alternative marker of M2 macrophages) in response to IL-10. We assume from our data that dramatic upregulation of CD163 by peripheral blood monocytes may have a pathophysiological role in early phases after kidney allograft transplantation and high pre-transplant expression of CD163 on blood monocytes might be involved in events leading to acute rejection.

• MeSH
• alografty MeSH
• antigen CD163 MeSH
• antigeny diferenciační myelomonocytární krev   MeSH
• biologické markery krev   MeSH
• CD antigeny krev   MeSH
• dospělí MeSH
• interleukin-10 metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• makrofágy imunologie   metabolismus   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• monocyty imunologie   metabolismus   MeSH
• receptory buněčného povrchu krev   MeSH
• rejekce štěpu krev   etiologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• transplantace ledvin * MeSH
• upregulace MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigen CD163 MeSH
• antigeny diferenciační myelomonocytární MeSH
• biologické markery MeSH
• CD antigeny MeSH
• IL10 protein, human MeSH Prohlížeč
• interleukin-10 MeSH
• receptory buněčného povrchu MeSH

Many patients with immunoglobulin A nephropathy (IgAN) progress to kidney failure even with optimal supportive care. An improved understanding of the pathophysiology of IgAN in recent years has led to the investigation of targeted therapies with acceptable tolerability that may address the underlying causes of IgAN or the pathogenesis of kidney injury. The complement system-particularly the lectin and alternative pathways of complement-has emerged as a key mediator of kidney injury in IgAN and a possible target for investigational therapy. This review will focus on the lectin pathway. The examination of kidney biopsies has consistently shown glomerular deposition of mannan-binding lectin (1 of 6 pattern-recognition molecules that activate the lectin pathway) together with IgA1 in up to 50% of patients with IgAN. Glomerular deposition of pattern-recognition molecules for the lectin pathway is associated with more severe glomerular damage and more severe proteinuria and hematuria. Emerging research suggests that the lectin pathway may also contribute to tubulointerstitial fibrosis in IgAN and that collectin-11 is a key mediator of this association. This review summarizes the growing scientific and clinical evidence supporting the role of the lectin pathway in IgAN and examines the possible therapeutic role of lectin pathway inhibition for these patients.

• Klíčová slova
• IgA nephropathy, complement, glomerulonephritis,
• MeSH
• glomerulus patologie   MeSH
• IgA nefropatie * patologie   MeSH
• imunoglobulin A metabolismus   MeSH
• ledviny patologie   MeSH
• lektiny metabolismus   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• imunoglobulin A MeSH
• lektiny MeSH

INTRODUCTION: Adjuvant immunotherapy has remarkably advanced the management of localized renal cell carcinoma (RCC) in patients at high risk of post-surgery recurrence. This Delphi study aimed to establish expert consensus on its use and subsequent management of relapse. METHODS: Fifteen RCC experts participated in a two-round Delphi process between July and November 2024. The study included 43 core survey items, divided into 67 components for comprehensive evaluation. RESULTS: Consensus, defined as ≥ 75 % agreement, was achieved for 39 of 67 items (58.2 %). Experts agreed on using the Leibovich score for selecting patients for adjuvant pembrolizumab (79 %), initiating therapy within 90 days post-surgery (86 %), and not restricting treatment to programmed death ligand-1 (PD-L1)-positive tumors (100 %). Plasma kidney injury molecule-1 (KIM-1) was considered by the experts as a potential useful recurrence risk biomarker (93 %). Immune checkpoint inhibitor (ICI)-refractory disease was defined as relapse within 6 months post-adjuvant therapy (80 %). Focal therapies for oligometastatic recurrence (80 %), and targeted therapies or clinical trial enrollment for ICI-refractory patients (87 %) were supported. Belzutifan was recommended for fourth-line or later use after ICI therapy and multiple tyrosine kinase inhibitors (93 %). By contrast, no consensus was reached on ICI salvage therapy in specific subgroups, including patients with clear-cell RCC (60 %), without bone/brain metastases (60 %), good performance status (60 %), low tumor burden (47 %), or papillary RCC (36 %). CONCLUSIONS: This Delphi study provides insights into the evolving role of adjuvant immunotherapy in localized RCC and relapse management. A multidisciplinary approach and periodic review are essential to optimizing treatment strategies.

• Klíčová slova
• Adjuvant immunotherapy, Consensus, Delphi, Relapse, Renal cell carcinoma,
• MeSH
• adjuvantní chemoterapie MeSH
• delfská metoda MeSH
• imunoterapie * metody   MeSH
• inhibitory kontrolních bodů terapeutické užití   MeSH
• karcinom z renálních buněk * farmakoterapie   terapie   patologie   imunologie   MeSH
• konsensus MeSH
• lidé MeSH
• lokální recidiva nádoru * MeSH
• nádory ledvin * patologie   farmakoterapie   terapie   imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• inhibitory kontrolních bodů MeSH

Cdc7 kinase regulates DNA replication. However, its role in DNA repair and recombination is poorly understood. Here we describe a pathway that stabilizes the human Cdc7-ASK (activator of S-phase kinase; also called Dbf4), its regulation, and its function in cellular responses to compromised DNA replication. Stalled DNA replication evoked stabilization of the Cdc7-ASK (Dbf4) complex in a manner dependent on ATR-Chk1-mediated checkpoint signaling and its interplay with the anaphase-promoting complex/cyclosome(Cdh1) (APC/C(Cdh1)) ubiquitin ligase. Mechanistically, Chk1 kinase inactivates APC/C(Cdh1) through degradation of Cdh1 upon replication block, thereby stabilizing APC/C(Cdh1) substrates, including Cdc7-ASK (Dbf4). Furthermore, motif C of ASK (Dbf4) interacts with the N-terminal region of RAD18 ubiquitin ligase, and this interaction is required for chromatin binding of RAD18. Impaired interaction of ASK (Dbf4) with RAD18 disables foci formation by RAD18 and hinders chromatin loading of translesion DNA polymerase η. These findings define a novel mechanism that orchestrates replication checkpoint signaling and ubiquitin-proteasome machinery with the DNA damage bypass pathway to guard against replication collapse under conditions of replication stress.

• Klíčová slova
• APC/CCdh1, Cdc7, Chk1, DNA lesion bypass, RAD18, replication stress,
• MeSH
• ATM protein metabolismus   MeSH
• CD antigeny MeSH
• checkpoint kinasa 1 MeSH
• geny APC fyziologie   MeSH
• HEK293 buňky MeSH
• HeLa buňky MeSH
• kadheriny metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• poškození DNA * MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• proteinkinasy metabolismus   MeSH
• proteiny buněčného cyklu genetika   metabolismus   MeSH
• replikace DNA * MeSH
• signální transdukce MeSH
• stabilita enzymů MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ATM protein MeSH
• ATR protein, human MeSH Prohlížeč
• CD antigeny MeSH
• CDC7 protein, human MeSH Prohlížeč
• CDH1 protein, human MeSH Prohlížeč
• checkpoint kinasa 1 MeSH
• CHEK1 protein, human MeSH Prohlížeč
• DBF4 protein, human MeSH Prohlížeč
• kadheriny MeSH
• protein-serin-threoninkinasy MeSH
• proteinkinasy MeSH
• proteiny buněčného cyklu MeSH

IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide. Current studies have shown that the Th17/Treg immune balance may be involved in the occurrence of IgAN, but the exact mechanism is still unclear. Indoleamine 2,3-dioxygenase (IDO) is an enzyme that catalyses degradation of tryptophan (Trp) through the kynurenine (Kyn) pathway; it can control inflammation and immune response by inducing Trp starvation. IDO may be a key molecule in regulating the Th17/Treg immune balance. However, it is not clear whether IDO is involved in the IgAN disease occurrence by regulating the Th17/Treg immune balance. In this study, an IgAN mouse model was established. The mice were intraperitoneally inoculated with IDO inhibitor 1-MT or agonist ISS-ODN to observe whether the IDO signalling pathway participates in the occurrence and development of IgAN by regulating the Th17/Treg immune balance. The results showed that IDO inhibitor 1-MT significantly increased renal injury and glomerular IgA accumulation and up-regulated Th17/Treg and Th17-related cytokine expression in IgAN mice, while ISS-ODN significantly decreased renal injury and glomerular IgA accumulation, down-regulated Th17/Treg expression and inhibited Th17-related cytokine expression in IgAN mice. In conclusion, IDO was involved in the occurrence and progress of IgAN by regulating the Th17/ Treg balance.

• MeSH
• buňky Th17 imunologie   MeSH
• cytokiny metabolismus   MeSH
• IgA nefropatie enzymologie   imunologie   MeSH
• imunita * MeSH
• indolamin-2,3,-dioxygenasa metabolismus   MeSH
• ledviny zranění   metabolismus   patologie   MeSH
• myši inbrední BALB C MeSH
• regulační T-lymfocyty imunologie   MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cytokiny MeSH
• indolamin-2,3,-dioxygenasa MeSH

Infection with the liver fluke Opisthorchis viverrini (Digenea) (Poirier, 1886) causes bile duct injury and periductal fibrosis by chronic overproduction of inflammatory-mediators and eventually results in cholangiocarcinoma development. While extensive research works have been done on O. viverrini infection-associated changes of bile ducts and periductal fibrosis, little attention was paid on morphological and biochemical changes of the bile canaliculi (BC), the origin of bile flow. We aimed to investigate the morphological and functional alterations of BC in the liver of hamsters infected with O. viverrini at one and three months post-infection. Ultrastructural changes of BC showed dilatation of BC and significant reduction of the density of microvilli as early as at one month post-infection. Immunohistochemistry revealed that CD10, a BC marker, expression was reduced early as one month post-infection. The mRNA expression of the genes encoding molecules related to bile secretion including bile acid uptake transporters (slc10a1 and slco1a1), bile acid dependent (abcb11) and independent (abcc2) bile flow and bile acid biosynthesis (cyp7a1 and cyp27a1) were significantly decreased at one month post-infection in association with the reduction of bile volume. In contrast, the expression of the mRNA of bile acid regulatory genes (fxr and shp-1) was significantly increased. These changes essentially persisted up to three months post-infection. In conclusion, O. viverrini infection induces morphological and functional changes of BC in association with the decrease of bile volume.

• MeSH
• játra ultrastruktura   MeSH
• křečci praví MeSH
• neprilysin genetika   metabolismus   MeSH
• Opisthorchis * MeSH
• opistorchióza parazitologie   patologie   MeSH
• regulace genové exprese MeSH
• žluč metabolismus   MeSH
• žlučové cesty metabolismus   parazitologie   patologie   ultrastruktura   MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• neprilysin MeSH