BK polyomavirus-associated nephropathy (PyVAN) is responsible for a significant percentage of transplanted kidneys prematurely terminating their function. Its occurrence is closely related to the intensity of immunosuppressive therapy. In a group of 161 newly transplanted patients, we prospectively evaluated 457 protocol renal biopsies performed within the first year after transplantation. Using the calcineurin inhibitors (CI) nephrotoxicity score, the incidence of nephrotoxicity was monitored as a manifestation of excessive immunosuppression. Findings were correlated with clinical evidence of active BK polyomavirus (BKPyV) replication and PyVAN. Compared to the normal histology, nephrotoxicity was associated with more frequent BKPyV viremia and viruria (p = .01 and p < .01, respectively) and more common occurrence of PyVAN. The persistence of toxicity in the subsequent biopsy proved to be a negative risk factor of viremia and viruria (p = .03 and p < .01, respectively), independently of the initial BKPyV status. Toxicity could also be used as a predictor of viremia and viruria (p = .04 and p < .01, respectively) even in the absence of viral replication at the time of initial biopsy. The early histological manifestation of CI nephrotoxicity was associated with significant BKPyV reactivation in the risky first posttransplant year.

• Klíčová slova
• BK polyomavirus-associated nephropathy, calcineurin inhibitors, kidney transplantation, nephrotoxicity, protocol biopsy,
• MeSH
• biopsie MeSH
• dospělí MeSH
• imunosupresivní léčba MeSH
• incidence MeSH
• infekce onkogenními viry virologie   MeSH
• inhibitory kalcineurinu škodlivé účinky   MeSH
• ledviny účinky léků   patologie   virologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nemoci ledvin chemicky indukované   MeSH
• polyomavirové infekce krev   moč   virologie   MeSH
• příjemce transplantátu MeSH
• prospektivní studie MeSH
• replikace viru účinky léků   MeSH
• rizikové faktory MeSH
• senioři MeSH
• transplantace ledvin škodlivé účinky   MeSH
• viremie MeSH
• virus BK účinky léků   fyziologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibitory kalcineurinu MeSH

OBJECTIVES: Little is known about the influence of calcineurin inhibitors on advanced oxidation protein products (AOPP) and total antioxidant status (TAS) after renal transplantation. DESIGN AND METHODS: AOPP and TAS were evaluated in transplanted patients on different calcineurin inhibitors. Thirty-five patients were treated with cyclosporine A (group A) and 33 with tacrolimus (group B). RESULTS: Over 6 months, the mean levels of AOPP in group A decreased from 205.9+/-125.7 to 140.9+/-78.9 micromol/L and TAS from 1.89+/-0.30 to 1.75+/-0.27 mmol/L. In group B, the mean levels of AOPP decreased from 196.5+/-123.9 to 129.6+/-63.8 micromol/L and TAS from 1.80+/-0.39 to 1.78+/-0.23 mmol/L. CONCLUSION: No significant differences in AOPP and TAS were found with respect to treatment. The only exception was the higher mean concentration of AOPP at month 1 in group A (p=0.026).

• MeSH
• antioxidancia metabolismus   MeSH
• chronické selhání ledvin metabolismus   rehabilitace   terapie   MeSH
• cyklosporin farmakologie   MeSH
• dospělí MeSH
• inhibitory enzymů farmakologie   MeSH
• inhibitory kalcineurinu * MeSH
• lidé středního věku MeSH
• lidé MeSH
• následné studie MeSH
• oxidační stres účinky léků   MeSH
• proteiny metabolismus   MeSH
• senioři MeSH
• takrolimus farmakologie   MeSH
• transplantace ledvin * rehabilitace   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antioxidancia MeSH
• cyklosporin MeSH
• inhibitory enzymů MeSH
• inhibitory kalcineurinu * MeSH
• proteiny MeSH
• takrolimus MeSH

Diffuse large B-cell lymphoma (DLBCL) represents the most common adult lymphoma and can be divided into 2 major molecular subtypes: the germinal center B-cell-like and the aggressive activated B-cell-like (ABC) DLBCL. Previous studies suggested that chronic B-cell receptor signaling and increased NF-κB activation contribute to ABC DLBCL survival. Here we show that the activity of the transcription factor NFAT is chronically elevated in both DLBCL subtypes. Surprisingly, NFAT activation is independent of B-cell receptor signaling, but mediated by an increased calcium flux and calcineurin-mediated dephosphorylation of NFAT. Intriguingly, although NFAT is activated in both DLBCL subtypes, long-term calcineurin inhibition with cyclosporin A or FK506, both clinically approved drugs, triggers potent cytotoxicity specifically in ABC DLBCL cells. The antitumor effects of calcineurin inhibitors are associated with the reduced expression of c-Jun, interleukin-6, and interleukin-10, which were identified as NFAT target genes that are particularly important for the survival of ABC DLBCL. Furthermore, calcineurin blockade synergized with BCL-2 and MCL-1 inhibitors in killing ABC DLBCL cells. Collectively, these findings identify constitutive NFAT signaling as a crucial functional driver of ABC DLBCL and highlight calcineurin inhibition as a novel strategy for the treatment of this aggressive lymphoma subtype.

• MeSH
• difúzní velkobuněčný B-lymfom farmakoterapie   metabolismus   patologie   MeSH
• inhibitory kalcineurinu farmakologie   MeSH
• kalcineurin chemie   MeSH
• lidé MeSH
• nádorové buňky kultivované MeSH
• proliferace buněk MeSH
• protein MCL-1 genetika   metabolismus   MeSH
• protoonkogenní proteiny c-bcl-2 genetika   metabolismus   MeSH
• transkripční faktory NFATC antagonisté a inhibitory   metabolismus   MeSH
• vápník metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibitory kalcineurinu MeSH
• kalcineurin MeSH
• MCL1 protein, human MeSH Prohlížeč
• protein MCL-1 MeSH
• protoonkogenní proteiny c-bcl-2 MeSH
• transkripční faktory NFATC MeSH
• vápník MeSH

Reflectance confocal microscopy (RCM) is a non-invasive, in vivo technique for real-time imaging of the epidermis and superficial dermis at the cellular resolution. We performed a pilot study focusing on the evaluation of the effect of topical corticosteroids and calcineurin inhibitors on the epidermis of patients with atopic dermatitis (AD). The effect was assessed by RCM. A total of 45 patients with AD took part in the study. Patients were selected according to the standardized protocol and divided into two groups. Twenty-three patients used methylprednisolone aceponat topically on the skin with lesions of AD once a day for three months (group A). Twenty-one patients applied topical tacrolimus on the skin with lesions of AD twice a day for three months (B). RCM imaging was performed on the day of intiating the study (T0), then after one (T1), two (T2) and three months (T3). In group A, there was a visible decrease of the stratum corneum and the epidermis thickness which was statistically significant. In comparison, in group B, such changes were not noted and the differences between the groups in time course were statistically significant. In group A, an increase in the percentage of blurred keratinocytes in the stratum spinosum was also recorded, especially between the first (T0) and the second visit (T1). RCM is a useful method for evaluating the changes in epidermis due to the different topical treatment in patients with AD.

• MeSH
• antiflogistika aplikace a dávkování   MeSH
• aplikace lokální MeSH
• atopická dermatitida farmakoterapie   metabolismus   patologie   MeSH
• časové faktory MeSH
• dítě MeSH
• dospělí MeSH
• inhibitory kalcineurinu aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• methylprednisolon aplikace a dávkování   analogy a deriváty   MeSH
• mladiství MeSH
• předškolní dítě MeSH
• senioři MeSH
• takrolimus aplikace a dávkování   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• dopisy MeSH
• klinické zkoušky MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• antiflogistika MeSH
• inhibitory kalcineurinu MeSH
• methylprednisolon MeSH
• methylprednisolone aceponate MeSH Prohlížeč
• takrolimus MeSH

BACKGROUND: The introduction of the calcineurin inhibitors (CI) cyclosporine and tacrolimus into immunosuppressive protocols initiated a new era in organ transplantation with excellent short-term graft survival. Nevertheless, the chronic nephrotoxicity of these drugs represents a significant adverse factor limiting their long-term use. Patients treated with a CI can be at risk for developing renal failure and this problem is especially pronounced in patients after renal transplantation. METHODS AND RESULTS: In a review paper we summarize the clinical aspects, histological manifestations and pitfalls of diagnostics of acute and chronic CI nephrotoxicity in patients after kidney transplantation. We look in detail at the disputed relationship between blood concentrations of cyclosporine and tacrolimus and histological manifestation of toxicity and summarize data showing that for toxic effects, local renal exposure to CI and their metabolites can play a more significant role than systemic exposure. We also include recent views on the pathophysiologic and molecular mechanisms underlying these changes; factors influencing local susceptibility to CI nephrotoxicity are discussed, including variability of expression and activity of P-glycoprotein and cytochrome P450. Last but not least we summarize our own experience with clinically manifest and subclinical forms of nephrotoxicity and their impact on the progression of chronic graft changes. CONCLUSIONS: Owing to their unique effects, CI remain the cornerstone of most immunosuppressive protocols for renal transplantation. Together with optimization of local kidney exposure to CI and their metabolites, efforts to reduce systemic levels as much as possible are the most important preventive measure for reducing toxic renal graft damage.

• MeSH
• cyklosporin škodlivé účinky   MeSH
• imunosupresiva škodlivé účinky   MeSH
• inhibitory kalcineurinu * MeSH
• ledviny účinky léků   MeSH
• lidé MeSH
• renální insuficience chemicky indukované   MeSH
• takrolimus škodlivé účinky   MeSH
• transplantace ledvin * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• cyklosporin MeSH
• imunosupresiva MeSH
• inhibitory kalcineurinu * MeSH
• takrolimus MeSH

Solid organ transplantation is an established treatment modality in patients with end-stage organ damage in cases where other therapeutic options fail. The long-term outcomes of solid organ transplant recipients have improved considerably since the introduction of the first calcineurin inhibitor (CNI) - cyclosporine. In 1984, the potent immunosuppressive properties of another CNI, tacrolimus, were discovered. The immunosuppressive effects of CNIs result from the inhibition of interleukin-2 synthesis and reduced proliferation of T cells due to calcineurin blockade. The considerable side effects that are associated with CNIs therapy include arterial hypertension and nephrotoxicity. The focus of this article was to review the available literature on the pathophysiological mechanisms of CNIs that induce chronic nephrotoxicity and arterial hypertension. CNIs lead to activation of the major vasoconstriction systems, such as the renin-angiotensin and endothelin systems, and increase sympathetic nerve activity. On the other hand, CNIs are known to inhibit NO synthesis and NO-mediated vasodilation and to increase free radical formation. Altogether, these processes cause endothelial dysfunction and contribute to the impairment of organ function. A better insight into the mechanisms underlying CNI nephrotoxicity could assist in developing more targeted therapies of arterial hypertension or preventing CNI nephrotoxicity in organ transplant recipients, including heart transplantation.

• MeSH
• hypertenze chemicky indukované   patologie   patofyziologie   MeSH
• imunosupresiva škodlivé účinky   MeSH
• inhibitory kalcineurinu aplikace a dávkování   škodlivé účinky   MeSH
• lidé MeSH
• nemoci ledvin chemicky indukované   patologie   patofyziologie   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• rejekce štěpu etiologie   prevence a kontrola   MeSH
• renin-angiotensin systém účinky léků   MeSH
• transplantace srdce škodlivé účinky   MeSH
• vazokonstrikce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• imunosupresiva MeSH
• inhibitory kalcineurinu MeSH
• reaktivní formy kyslíku MeSH

The purpose of the prospective study was to determine the prevalence of subclinical toxicity of calcineurin inhibitors (CI) in repeated protocol renal allograft biopsies and to assess its impact on the development of chronic graft changes. A total of 424 biopsies were conducted in a cohort of 158 patients; of these biopsies, 158 were in the third week, 142 were in the third month and 124 were in the first year after transplantation. Histological signs of toxicity occurred in the third week in 33 (20.1%) patients, with persistence after CI dose reduction in the third month in 27 (19.0%) and in the first year in 23 (18.5%) patients. Of the toxic changes, 52% were clinically silent. At the end of the one-year follow-up, both subclinical and clinically manifest toxicity resulted in a similar progression of chronic changes quantified by Banff chronicity score and they significantly differed from the control group (P < 0.05). Subclinical toxicity affects a significant percentage of grafts; it occurs independently of dosage, blood level and type of applied CI. It is associated with the progression of chronic changes as early as in the first year after transplantation and represents an independent risk factor for chronic allograft damage. We report here our clinical approach to toxicity.

• MeSH
• biopsie metody   MeSH
• chronické selhání ledvin farmakoterapie   terapie   MeSH
• dospělí MeSH
• homologní transplantace škodlivé účinky   MeSH
• imunosupresiva škodlivé účinky   toxicita   MeSH
• inhibitory kalcineurinu * MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• následné studie MeSH
• progrese nemoci MeSH
• prospektivní studie MeSH
• rizikové faktory MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• imunosupresiva MeSH
• inhibitory kalcineurinu * MeSH

Calcineurin is required for oocyte exit from meiotic block in metaphase II (MII) stage in invertebrates and also in lower vertebrates. However, the role of calcineurin in mammalian oocyte activation is still unclear. The aim of this study was to determine whether calcineurin is involved in the processes regulating porcine oocyte activation. Indirect immunofluorescence demonstrated localization of both calcineurin subunits, CnA and CnB, especially in the cortex area of MII oocytes, in vitro fertilized and also parthenogenetically activated oocytes. After activation, the fluorescence intensity of the protein in the cortex area of oocytes remains unchanged; the protein calcineurin in the cytoplasm was recorded mainly around the pronuclei. Treatment of matured oocytes with calcineurin inhibitors, cyclosporin A (CsA) and hymenistatin I (HS-I), followed by activation with calcium ionophore A23187, significantly decreased the rate of activated oocytes compared to oocytes that were treated only with calcium ionophore (Ca-Io), (CsA+Ca-Io 25.0% v. Ca-Io 83.3%; HS-I+Ca-Io 32.5% v. Ca-Io 85.0%). Compared to the control, CsA treatment of matured oocytes followed by activation with Ca-Io did not affect the activity level of metaphase-promoting factor (MPF) and mitogen-activated protein kinase (MAPK) in activated oocytes evaluated by kinase activity assay. Simultaneous staining of calcineurin and cortical granule content in matured oocytes showed that calcineurin distributed in the cortical area of the oocyte has not been colocalized with cortical granules content. On the other hand, the calcineurin inhibition before parthenogenetic activation leads to a reduction of the cortical reaction level compared to oocytes that were not treated with CsA (complete exocytosis: CsA+Ca-Io 2.6% v. Ca-Io 83.9%; sum of cortical granule brightness: CsA + Ca-Io 0.69 v. Ca-Io 0.15). Our results showed that calcineurin is involved in the process of pig oocyte activation and cortical granule exocytosis; however this regulation seems to be MPF and MAPK independent.

• Klíčová slova
• activation, calcineurin, cortical granule exocytosis, oocyte, pig,
• MeSH
• exocytóza MeSH
• fertilizace in vitro MeSH
• ionofory kalciové farmakologie   MeSH
• IVM techniky veterinární   MeSH
• kalcineurin farmakologie   MeSH
• metafáze MeSH
• oocyty účinky léků   metabolismus   MeSH
• partenogeneze fyziologie   MeSH
• prasata fyziologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ionofory kalciové MeSH
• kalcineurin MeSH

Calcineurin (CN) inhibitors are effective clinical immunosuppressants but leave patients vulnerable to potentially fatal fungal infections. This study tested the hypothesis that CN inhibition interferes with antifungal immune defenses mediated by monocytes. We showed that NFAT is expressed by human monocytes, and is activated by exposure to fungal ligands. We confirmed that NFAT translocation potently activated target gene transcription using a human monocytic reporter cell line. Inhibition of CN-NFAT by cyclosporine A significantly reduced monocyte production of TNF-α, IL-10, and MCP-1 proteins in response to pattern recognition receptor ligands as well as to Aspergillus fumigatus conidia. Moreover, we revealed that human monocytes express the antifungal protein pentraxin-3 under control of NFAT. In conclusion, clinical CN inhibitors have the potential to interfere with the novel NFAT-dependent pentraxin-3 pathway as well as antifungal cytokine production in human monocytes, thereby impeding monocyte-mediated defenses against fungal infection in immune-suppressed patients.

• Klíčová slova
• Tacrolimus, antifungal response, cyclosporine A, pattern recognition receptor signaling,
• MeSH
• antifungální látky metabolismus   MeSH
• Aspergillus fumigatus účinky léků   MeSH
• C-reaktivní protein metabolismus   MeSH
• chemokiny metabolismus   MeSH
• cyklosporin farmakologie   MeSH
• inhibitory kalcineurinu farmakologie   MeSH
• interleukin-10 metabolismus   MeSH
• lidé MeSH
• monocyty účinky léků   metabolismus   MeSH
• myeloidní buňky účinky léků   metabolismus   MeSH
• myši MeSH
• sekvence nukleotidů MeSH
• sekvenční homologie aminokyselin MeSH
• sérový amyloidový protein metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• THP-1 buňky MeSH
• TNF-alfa metabolismus   MeSH
• transkripční faktory NFATC metabolismus   MeSH
• transport proteinů účinky léků   MeSH
• vazebná místa MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antifungální látky MeSH
• C-reaktivní protein MeSH
• chemokiny MeSH
• cyklosporin MeSH
• inhibitory kalcineurinu MeSH
• interleukin-10 MeSH
• PTX3 protein MeSH Prohlížeč
• sérový amyloidový protein MeSH
• TNF-alfa MeSH
• transkripční faktory NFATC MeSH

Treatment of post-transplant patients with immunosuppressive drugs targeting the calcineurin-nuclear factor of activated T cells (NFAT) pathway, including cyclosporine A or tacrolimus, is commonly associated with a higher incidence of opportunistic infections, such as Aspergillus fumigatus, which can lead to severe life-threatening conditions. A component of the A. fumigatus cell wall, β-glucan, is recognized by dendritic cells (DCs) via the Dectin-1 receptor, triggering downstream signaling that leads to calcineurin-NFAT binding, NFAT translocation, and transcription of NFAT-regulated genes. Here, we address the question of whether calcineurin signaling in CD11c-expressing cells, such as DCs, has a specific role in the innate control of A. fumigatus. Impairment of calcineurin in CD11c-expressing cells (CD11ccrecnb1loxP) significantly increased susceptibility to systemic A. fumigatus infection and to intranasal infection in irradiated mice undergoing bone marrow transplant. Global expression profiling of bone marrow-derived DCs identified calcineurin-regulated processes in the immune response to infection, including expression of pentraxin-3, an important antifungal defense protein. These results suggest that calcineurin inhibition directly impairs important immunoprotective functions of myeloid cells, as shown by the higher susceptibility of CD11ccrecnbloxP mice in models of systemic and invasive pulmonary aspergillosis, including after allogeneic bone marrow transplantation. These findings are relevant to the clinical management of transplant patients with severe Aspergillus infections.

• MeSH
• antigeny CD11c metabolismus   MeSH
• Aspergillus fumigatus imunologie   MeSH
• aspergilóza imunologie   MeSH
• C-reaktivní protein genetika   metabolismus   MeSH
• dendritické buňky imunologie   MeSH
• down regulace MeSH
• imunosupresiva škodlivé účinky   terapeutické užití   MeSH
• inhibitory kalcineurinu škodlivé účinky   terapeutické užití   MeSH
• kalcineurin genetika   metabolismus   MeSH
• kultivované buňky MeSH
• lidé MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• náchylnost k nemoci MeSH
• rejekce štěpu prevence a kontrola   MeSH
• sérový amyloidový protein genetika   metabolismus   MeSH
• signální transdukce MeSH
• transplantace kostní dřeně * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny CD11c MeSH
• C-reaktivní protein MeSH
• imunosupresiva MeSH
• inhibitory kalcineurinu MeSH
• kalcineurin MeSH
• PTX3 protein MeSH Prohlížeč
• sérový amyloidový protein MeSH