Necroptosis has been recognized in heart failure (HF). In this study, we investigated detailed necroptotic signalling in infarcted and non-infarcted areas separately and its mechanistic link with main features of HF. Post-infarction HF in rats was induced by left coronary occlusion (60 minutes) followed by 42-day reperfusion. Heart function was assessed echocardiographically. Molecular signalling and proposed mechanisms (oxidative stress, collagen deposition and inflammation) were investigated in whole hearts and in subcellular fractions when appropriate. In post-infarction failing hearts, TNF and pSer229-RIP3 levels were comparably increased in both infarcted and non-infarcted areas. Its cytotoxic downstream molecule p-MLKL, indicating necroptosis execution, was detected in infarcted area. In non-infarcted area, despite increased pSer229-RIP3, p-MLKL was present in neither whole cells nor the cell membrane known to be associated with necroptosis execution. Likewise, increased membrane lipoperoxidation and NOX2 levels unlikely promoted pro-necroptotic environment in non-infarcted area. Collagen deposition and the inflammatory csp-1-IL-1β axis were active in both areas of failing hearts, while being more pronounced in infarcted tissue. Although apoptotic proteins were differently expressed in infarcted and non-infarcted tissue, apoptosis was found to play an insignificant role. p-MLKL-driven necroptosis and inflammation while inflammation only (without necroptotic cell death) seem to underlie fibrotic healing and progressive injury in infarcted and non-infarcted areas of failing hearts, respectively. Upregulation of pSer229-RIP3 in both HF areas suggests that this kinase, associated with both necroptosis and inflammation, is likely to play a dual role in HF progression.

• MeSH
• apoptóza fyziologie   MeSH
• buněčná smrt fyziologie   MeSH
• infarkt myokardu metabolismus   MeSH
• kardiomyocyty metabolismus   MeSH
• krysa rodu rattus MeSH
• nekroptóza fyziologie   MeSH
• nekróza metabolismus   MeSH
• oxidační stres fyziologie   MeSH
• potkani Sprague-Dawley MeSH
• serin-threoninkinasy interagující s receptory metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• srdeční selhání metabolismus   MeSH
• upregulace fyziologie   MeSH
• zánět metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The fads2 gene encoding delta6-desaturase, the rate-limiting enzyme of the LCPUFA biosynthesis is expressed in astrocytes. Dietary fatty acids, which cross the blood-brain barrier, may regulate the transcription of lipogenic enzymes through activation of transcription factors such as peroxisome proliferator-activated receptors (PPARs). The PPARs form the transcription complex with retinoid X receptors (RXRs) that are activated by 9-cis retinoic acid, a metabolite of vitamin A (VA). The study examines whether challenge of astrocytes with VA, prior 24-h treatment with palmitic acid (PA), alpha-linolenic acid (ALA) or docosahexaenoic acid (DHA) has the effect on the FADS2 expression. RT-qPCR showed that in astrocytes not challenged with VA, PA increased fads2 gene expression and DHA decreased it. However, in VA-primed astrocytes, PA doubled the FADS2 mRNA levels, while DHA increased fads2 gene expression, oppositely to non-primed cells. Furthermore, similar changes were seen in VA-primed astrocytes with regard to delta6-desaturase protein levels following PA and DHA treatment. ALA did not have any effect on the FADS2 mRNA and protein levels in either VA-primed or non-primed astrocytes. These findings indicate that in the presence of vitamin A, DHA upregulates fads2 gene expression in astrocytes.

• MeSH
• astrocyty účinky léků   metabolismus   MeSH
• exprese genu MeSH
• krysa rodu rattus MeSH
• kultivované buňky MeSH
• kyseliny dokosahexaenové farmakologie   MeSH
• mozková kůra účinky léků   metabolismus   MeSH
• novorozená zvířata MeSH
• potkani Wistar MeSH
• stearyl-CoA-desaturasa biosyntéza   genetika   MeSH
• upregulace účinky léků   fyziologie   MeSH
• vitamin A farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

We examined the upregulation of ET-1/ETBR/eNOS signaling in renoprotective effect of vitamin D in kidney fibrosis model in mice using unilateral ureteral obstruction (UUO). One group was treated with intraperitoneal injection of 0.125 mg/kg of Calcitriol (UUO+VD). Vascular remodeling was quantified based on lumen area and lumen/wall area ratio (LWAR) of intrarenal arteries using Sirius Red staining. ET-1, ETBR, eNOS, CD31 and VEGF mRNA expressions were quantified using qRT-PCR. Focusing on endothelin-1 (ET-1) signaling in endothelial cells (EC), siRNA of ET-1 was performed in human umbilical vein endothelial cells (HUVEC) for reducing ET-1 expression. Then HUVECs were treated with and without 100 nM Calcitriol treatment in hypoxic and normoxic conditions to elucidate ET-1/eNOS signaling. Our in vivo study revealed vascular remodeling and renal ischemia attenuation after Calcitriol treatment. Vascular remodeling was attenuated in the UUO+VD group as shown by increasing lumen areas and LWAR in intrarenal arteries. These findings were associated with significant higher CD31 and VEGF mRNA expression compared to the UUO group. Vitamin D treatment also increased ET-1, ETBR and eNOS mRNA expressions. Our in vitro study demonstrated Calcitriol induced ET-1 and eNOS mRNA expressions upregulation in HUVEC under normoxic and hypoxic condition. Meanwhile, siRNA for ET-1 inhibited the upregulation of eNOS mRNA expression after Calcitriol treatment. Vitamin D ameliorates kidney fibrosis through attenuating vascular remodeling and ischemia with upregulating ET-1/ETBR and eNOS expression.

• MeSH
• endoteliální buňky pupečníkové žíly (lidské) MeSH
• endotelin-1 biosyntéza   MeSH
• fibróza MeSH
• ischemie farmakoterapie   metabolismus   MeSH
• lidé MeSH
• messenger RNA biosyntéza   MeSH
• myši MeSH
• nemoci ledvin farmakoterapie   metabolismus   MeSH
• receptor endotelinu B biosyntéza   MeSH
• remodelace cév účinky léků   fyziologie   MeSH
• synthasa oxidu dusnatého, typ III biosyntéza   MeSH
• upregulace účinky léků   fyziologie   MeSH
• vitamin D farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE: ROR1, a receptor in the noncanonical Wnt/planar cell polarity (PCP) pathway, is upregulated in malignant B cells of chronic lymphocytic leukemia (CLL) patients. It has been shown that the Wnt/PCP pathway drives pathogenesis of CLL, but which factors activate the ROR1 and PCP pathway in CLL cells remains unclear. EXPERIMENTAL DESIGN: B lymphocytes from the peripheral blood of CLL patients were negatively separated using RosetteSep (StemCell) and gradient density centrifugation. Relative expression of WNT5A, WNT5B, and ROR1 was assessed by quantitative real-time PCR. Protein levels, protein interaction, and downstream signaling were analyzed by immunoprecipitation and Western blotting. Migration capacity of primary CLL cells was analyzed by the Transwell migration assay. RESULTS: By analyzing the expression in 137 previously untreated CLL patients, we demonstrate that WNT5A and WNT5B genes show dramatically (five orders of magnitude) varying expression in CLL cells. High WNT5A and WNT5B expression strongly associates with unmutated IGHV and shortened time to first treatment. In addition, WNT5A levels associate, independent of IGHV status, with the clinically worst CLL subgroups characterized by dysfunctional p53 and mutated SF3B1. We provide functional evidence that WNT5A-positive primary CLL cells have increased motility and attenuated chemotaxis toward CXCL12 and CCL19 that can be overcome by inhibitors of Wnt/PCP signaling. CONCLUSIONS: These observations identify Wnt-5a as the crucial regulator of ROR1 activity in CLL and suggest that the autocrine Wnt-5a signaling pathway allows CLL cells to overcome natural microenvironmental regulation.

• MeSH
• autokrinní signalizace fyziologie   MeSH
• B-lymfocyty metabolismus   MeSH
• chemotaxe fyziologie   MeSH
• chronická lymfatická leukemie metabolismus   MeSH
• HEK293 buňky MeSH
• lidé MeSH
• pohyb buněk fyziologie   MeSH
• proteiny Wnt metabolismus   MeSH
• protoonkogenní proteiny metabolismus   MeSH
• regulace genové exprese u nádorů fyziologie   MeSH
• signální dráha Wnt fyziologie   MeSH
• sirotčí receptory podobné receptoru tyrosinkinasy metabolismus   MeSH
• upregulace fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Intramural MeSH

BACKGROUND: Na(+)/H(+) exchanger-1 (NHE-1) is involved in pH regulation and is up-regulated in different malignancies. Activation of NHE-1 is one way for allowing cells to avoid intracellular acidification and protect them against apoptosis. Inhibitors of NHE-1 are able to decrease intracellular pH and induce apoptosis. Some statins can also act by partial inhibition of NHE-1. This review presents progress in understanding the mechanisms of action of these inhibitors, connections with certain genetic mutations and acquired treatment resistance, as well as new patents on them. METHODS: A MEDLINE search for original and review articles using key terms, Na(+)/H(+) exchanger, leukemia, cariporide, and amiloride. Recent patents with NHE-1 inhibitors published by United States Patent and Trademark Office are also presented. RESULTS AND CONCLUSIONS: Sorafenib is used for the treatment of acute myeloid leukemia patients carrying internal tandem duplication of fms-like tyrosine kinase 3 (FLT3-ITD) mutation. 5-(N, N-hexamethylene)-amiloride can increase the suppression of FLT3 signaling by sorafenib. NHE-1 inhibitors are able to increase the sensitivity of chronic myeloid leukemia cells to tyrosine kinase inhibitors, including through the inhibition of P-glycoprotein. NHE-1 inhibitors are promising adjuvant drugs for overcoming acquired resistance to treatment in various malignant hemopathies.

• MeSH
• akutní myeloidní leukemie farmakoterapie   genetika   MeSH
• amilorid farmakologie   MeSH
• apoptóza účinky léků   MeSH
• chronická myeloidní leukemie farmakoterapie   genetika   MeSH
• fenylmočovinové sloučeniny farmakologie   MeSH
• geny abl genetika   MeSH
• guanidiny farmakologie   MeSH
• hemoxygenasa-1 antagonisté a inhibitory   metabolismus   MeSH
• imatinib mesylát farmakologie   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• koncentrace vodíkových iontů MeSH
• lékové interakce MeSH
• lidé MeSH
• mutace genetika   MeSH
• Na(+)-H(+) antiport antagonisté a inhibitory   fyziologie   MeSH
• nádorová hypoxie fyziologie   MeSH
• nádorové buněčné linie MeSH
• niacinamid analogy a deriváty   farmakologie   MeSH
• osmolární koncentrace MeSH
• patenty jako téma MeSH
• poškození DNA fyziologie   MeSH
• proteiny přenášející kationty antagonisté a inhibitory   fyziologie   MeSH
• protinádorové látky farmakologie   MeSH
• signální transdukce účinky léků   MeSH
• statiny farmakokinetika   MeSH
• sulfony farmakologie   MeSH
• tyrosinkinasa 3 podobná fms antagonisté a inhibitory   genetika   MeSH
• upregulace fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Ergot alkaloids are widely used in the pharmaceutical industry in drug preparations for treating migraines and Parkinson's disease, inducing uterine contraction, and other purposes. Phytopathogenic fungi of the genus Claviceps (e.g. C. purpurea) comprise a major biological source of ergot alkaloids. Worldwide industrial production of these alkaloids derives almost equally from two biotechnological procedures: submerged culture of the fungus in fermenters and field parasitic production in dormant fungal organs known as sclerotia (also termed ergot). Ergot yields from field cultivation are greatly affected by weather and also can be much reduced by pollen contamination from imperfectly male-sterile rye, as only unfertilized ovaries can be infected by C. purpurea spores. Two substances with gametocidal effect - maleic hydrazide and 2-chloroethylphosphonic acid - were tested during three consecutive seasons in small field experiments for the ability to induce or amplify the male sterility of rye as well as the impacts on germination of C. purpurea spores and general vitality of rye host plants. Maleic hydrazide was proven to be a highly effective gametocide on both a fertile rye variety and a variety with imperfectly induced cytoplasmic male sterility. It showed negligible effect on germination of C. purpurea spores. Both accurate dosaging of the active gametocidal compound and timing of the application just 2-3 weeks before onset of anthesis proved crucial to achieving high ergot yield with minimum grain impurities.

• MeSH
• hydrazid kyseliny maleinové aplikace a dávkování   MeSH
• námelové alkaloidy biosyntéza   izolace a purifikace   MeSH
• neplodnost rostlin účinky léků   fyziologie   MeSH
• organofosforové sloučeniny aplikace a dávkování   MeSH
• regulátory růstu rostlin farmakologie   MeSH
• upregulace účinky léků   fyziologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zárodečné buňky rostlin účinky léků   MeSH
• žito účinky léků   metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVES: S100A4 has been implicated in cancer and several inflammatory diseases, including RA. The aim of the present study was to determine whether S100A4 can stimulate proinflammatory cytokine production in mononuclear cells. METHODS: Peripheral blood mononuclear cells (PBMCs) isolated from patients with RA were stimulated with S100A4, S100A8, S100A9 and S100A12. The production of IL-1β, IL-6 and TNF-α was measured by ELISA. Receptor for advanced glycation end products (RAGEs) and Toll-like receptor 4 (TLR4) signalling were examined. For signalling pathway blocking studies, inhibitors of myeloid differentiation primary response gene 88 (MyD88), nuclear factor kappa B (NF-κB) and the mitogen activated protein (MAP) kinases p38, extracellular signal-regulated kinase 1/2 (ERK1/2) and Jun N-terminal kinase (JNK) were used. MAP kinase activation was evaluated by western blotting. RESULTS: Stimulation of PBMCs with S100A4 significantly up-regulated IL-1β, IL-6 and TNF-α production compared with unstimulated cells (P < 0.001). Importantly, the production of these cytokines was markedly enhanced in response to S100A4 compared with S100A8 and S100A12; however, it was less pronounced compared with S100A9. Furthermore, enhanced production of proinflammatory cytokines in S100A4-stimulated PMBCs was at least partly mediated via TLR4, but not RAGEs, and by activation of the transcription factor NF-κB and the MAP kinases p38 and ERK1/2. CONCLUSION: This is the first study to demonstrate that S100A4 can induce an inflammatory response mediated by TLR4 and by the activation of NF-κB and the kinases p38 and ERK1/2 in mononuclear cells from patients with RA. Therefore S100A4 may be a potential therapeutic target for immune-mediated diseases.

• MeSH
• cytokiny metabolismus   MeSH
• dospělí MeSH
• leukocyty mononukleární metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• NF-kappa B metabolismus   MeSH
• proteiny S100 metabolismus   MeSH
• revmatoidní artritida metabolismus   MeSH
• senioři MeSH
• signální transdukce fyziologie   MeSH
• toll-like receptor 4 metabolismus   MeSH
• upregulace fyziologie   MeSH
• zánět metabolismus   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

A selection of tert-butylhydroperoxide (tBOOH)-tolerant Candida albicans mutants showed increased tolerances to 19 different stress conditions. These mutants are characterized by a constitutively upregulated antioxidative defense system and, therefore, adaptation to oxidative stress may play an important role in gaining general stress tolerance in C. albicans. Although C. albicans cells may undergo morphological transitions under various stress treatments, this ability shows considerable stress-specific and strain-specific variability and, hence, it is independent of mounting stress cross protections.

• MeSH
• antioxidancia fyziologie   MeSH
• Candida albicans genetika   fyziologie   ultrastruktura   MeSH
• fluorescenční mikroskopie MeSH
• fyziologická adaptace genetika   fyziologie   MeSH
• mikroskopie fázově kontrastní MeSH
• mutace genetika   fyziologie   MeSH
• oxidační stres genetika   fyziologie   MeSH
• upregulace genetika   fyziologie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The aim of this study was to examine whether threshold to heat stimuli, and expression of transient receptor potential vanilloid1 (TRPV1) and nerve growth factor (NGF) in dorsal root ganglion (DRG) altered under conditions of long-term limb immobilization. A plastic cast was wrapped around the right limb from the forearm to the forepaw to keep wrist joint at 90° of flexion for 5 weeks. Heat hyperalgesia was tested using the plantar test at 6 h after removing cast. The rats were perfused transcardially with 4 % paraformaldehyde and DRGs were excised at 24 h after removing cast. For size distributions of the TRPV1-IR and NGF-IR neuronal profile, the DRG area measurements over 1000 DRG neurons per animal were measured in each side, on both the immobilized (ipsilateral) and contralateral sides. Ipsilateral withdrawal latency was significantly shorter than contralateral sides. Ipsilateral percentage of immunoreactive neurons in the total DRG neurons was significantly higher than contralateral sides in TRPV1-IR and NGF-IR. Long-term casting induced heat hyperalgesia, and up-regulation and phenotypic change of TRPV1-IR and NGF-IR in DRGs on the immobilized side. These DRG alterations may involve heat hyperalgesia after long-term limb immobilization.

• MeSH
• hyperalgezie genetika   MeSH
• imobilizace * MeSH
• kationtové kanály TRPV biosyntéza   genetika   MeSH
• klouby fyziologie   MeSH
• krysa rodu rattus MeSH
• nervový růstový faktor biosyntéza   MeSH
• neurony účinky léků   MeSH
• práh bolesti účinky léků   MeSH
• spinální ganglia metabolismus   MeSH
• upregulace fyziologie   MeSH
• vysoká teplota škodlivé účinky   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Erythropoietin (EPO), known for its role in erythroid differentiation, has been suggested to have a direct protective role against a variety of neurotoxic insults. In the present study, we investigated the expression of EPO receptor (EPOR) and the number of EPORpositive cells in three encephalic regions (ventral mesencephalon, striatum, cortex) following lesion induced by 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP). C57BL/6 mice underwent intraperitoneal injection of MPTP at 24 h intervals for 5 days, and their brains were examined 1, 2, 4, 7, 14 or 21 days after the last injection. Western blot and immunohistochemistry analysis revealed that EPOR was dramatically up-regulated in the ventral mesencephalon, 4 days after MPTP insult until the day 21. In contrast, there was a baseline level of EPOR in the striatum and cortex. At subsequent time points after MPTP injury, the levels of EPOR in the two regions were not statistically different compared with those in normal animals. These results suggest that the regional specific up-regulation of EPOR at an early stage after MPTP stimulus may represent a pro-survival mechanism against neurotoxin injury in Parkinsonian model.

• MeSH
• corpus striatum metabolismus   MeSH
• financování organizované MeSH
• imunohistochemie MeSH
• modely nemocí na zvířatech MeSH
• mozková kůra metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• parkinsonské poruchy metabolismus   MeSH
• receptory erythropoetinu metabolismus   MeSH
• substantia nigra metabolismus   MeSH
• upregulace fyziologie   MeSH
• western blotting MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH