V tomto článku se budeme věnovat chronologicky objevům, resp. hypotézám, které souvisejí právě s Alzheimerovou-Fischerovou chorobou, a to hlavně v kontextu patofyziologie. V rámci pochopení návaznosti jsou jako první zmíněny patologické nálezy, jelikož na jejich základě byly hypotézy postupně vytvářeny. Vzhledem k obrovskému rozsahu jsme se však snažili vybrat pouze některé hypotézy, které jsou nejčastěji zmiňovány nebo z našeho pohledu nejzajímavější. Naším cílem není detailně zmapovat celou novodobou historii, proto se z úvodu 20. století rovnou přesuneme do jeho druhé poloviny. Demence se v tomto období postupně stávaly čím dál větším lékařským a společenským problémem, technologické možnosti zase postupně otevíraly nové možnosti výzkumu.

In this article, we will look at discoveries and hypotheses that were through time linked to Alzheimer‘s-Fischer disease, mainly in the con- text of pathophysiology. As part of the understanding of the link, pathological findings are mentioned first, as on the basis of these, the hypotheses were gradually developed. However, given the enormous scale, we have tried to select only some of the hypotheses that are most frequently mentioned or, from our point of view, the most interesting. Our goal is not to map in detail all of modern history, so we will move directly from the beginning of the 20th century to its second half. Dementia gradually became a growing medical and social problem during this period, while technological possibilities opened up new avenues of research.

• MeSH
• Alzheimerova nemoc * dějiny   patofyziologie   patologie   MeSH
• amyloidový prekurzorový protein beta * dějiny   škodlivé účinky   MeSH
• dějiny 20. století MeSH
• dějiny 21. století MeSH
• glukokortikoidy škodlivé účinky   MeSH
• hyperinzulinismus komplikace   MeSH
• lidé MeSH
• melatonin fyziologie   MeSH
• mitochondriální membrány patologie   MeSH
• mozek anatomie a histologie   metabolismus   patologie   MeSH
• mozková kůra anatomie a histologie   patologie   MeSH
• neurony patologie   MeSH
• střevní mikroflóra MeSH
• zinek nedostatek   MeSH
• Check Tag
• dějiny 20. století MeSH
• dějiny 21. století MeSH
• lidé MeSH
• Publikační typ
• historické články MeSH

The identification of compounds which protect the double-membrane of mitochondrial organelles from disruption by toxic confomers of amyloid proteins may offer a therapeutic strategy to combat human neurodegenerative diseases. Here, we exploited an extract from the marine brown seaweed Padina pavonica (PPE) as a vital source of natural bioactive compounds to protect mitochondrial membranes against insult by oligomeric aggregates of the amyloidogenic proteins amyloid-β (Aβ), α-synuclein (α-syn) and tau, which are currently considered to be major targets for drug discovery in Alzheimer's disease (AD) and Parkinson's disease (PD). We show that PPE manifested a significant inhibitory effect against swelling of isolated mitochondria exposed to the amyloid oligomers, and attenuated the release of cytochrome c from the mitochondria. Using cardiolipin-enriched synthetic lipid membranes, we also show that dye leakage from fluorophore-loaded vesicles and formation of channel-like pores in planar bilayer membranes are largely prevented by incubating the oligomeric aggregates with PPE. Lastly, we demonstrate that PPE curtails the ability of Aβ42 and α-syn monomers to self-assemble into larger β-aggregate structures, as well as potently disrupts their respective amyloid fibrils. In conclusion, the mito-protective and anti-aggregator biological activities of Padina pavonica extract may be of therapeutic value in neurodegenerative proteinopathies, such as AD and PD.

• MeSH
• alfa-synuklein metabolismus   toxicita   MeSH
• amyloidní beta-protein metabolismus   toxicita   MeSH
• lidé MeSH
• lipidové dvojvrstvy chemie   MeSH
• mitochondriální membrány účinky léků   patologie   MeSH
• mořské řasy chemie   MeSH
• neuroprotektivní látky chemie   farmakologie   MeSH
• peptidové fragmenty metabolismus   toxicita   MeSH
• permeabilita buněčné membrány účinky léků   MeSH
• Phaeophyceae chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Pancreatic β-cells are vulnerable to oxidative stress due to their low content of redox buffers, such as glutathione, but possess a rich content of thioredoxin, peroxiredoxin, and other proteins capable of redox relay, transferring redox signaling. Consequently, it may be predicted that cytosolic antioxidants could interfere with the cytosolic redox signaling and should not be recommended for any potential therapy. In contrast, mitochondrial matrix-targeted antioxidants could prevent the primary oxidative stress arising from the primary superoxide sources within the mitochondrial matrix, such as at the flavin (IF) and ubiquinone (IQ) sites of superoxide formation within respiratory chain complex I and the outer ubiquinone site (IIIQ) of complex III. Therefore, using time-resolved confocal fluorescence monitoring with MitoSOX Red, we investigated various effects of mitochondria-targeted antioxidants in model pancreatic β-cells (insulinoma INS-1E cells) and pancreatic islets. Both SkQ1 (a mitochondria-targeted plastoquinone) and a suppressor of complex III site Q electron leak (S3QEL) prevented superoxide production released to the mitochondrial matrix in INS-1E cells with stimulatory glucose, where SkQ1 also exhibited an antioxidant role for UCP2-silenced cells. SkQ1 acted similarly at nonstimulatory glucose but not in UCP2-silenced cells. Thus, UCP2 can facilitate the antioxidant mechanism based on SkQ1+ fatty acid anion- pairing. The elevated superoxide formation induced by antimycin A was largely prevented by S3QEL, and that induced by rotenone was decreased by SkQ1 and S3QEL and slightly by S1QEL, acting at complex I site Q. Similar results were obtained with the MitoB probe, for the LC-MS-based assessment of the 4 hr accumulation of reactive oxygen species within the mitochondrial matrix but for isolated pancreatic islets. For 2 hr INS-1E incubations, some samples were influenced by the cell death during the experiment. Due to the frequent dependency of antioxidant effects on metabolic modes, we suggest a potential use of mitochondria-targeted antioxidants for the treatment of prediabetic states after cautious nutrition-controlled tests. Their targeted delivery might eventually attenuate the vicious spiral leading to type 2 diabetes.

• MeSH
• antioxidancia farmakologie   MeSH
• beta-buňky účinky léků   metabolismus   patologie   MeSH
• fenantridiny MeSH
• kultivované buňky MeSH
• mitochondriální membrány účinky léků   metabolismus   patologie   MeSH
• mitochondrie účinky léků   metabolismus   patologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• organofosforové sloučeniny MeSH
• oxidace-redukce MeSH
• oxidační stres účinky léků   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• uncoupling protein 2 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

• Klíčová slova
• mitochondriální pór přechodné propustnosti,
• MeSH
• akutní nekrotizující pankreatitida patologie   MeSH
• Alzheimerova nemoc etiologie   MeSH
• amyotrofická laterální skleróza etiologie   MeSH
• buňky metabolismus   MeSH
• Huntingtonova nemoc etiologie   MeSH
• ionty chemie   MeSH
• kardiovaskulární nemoci MeSH
• mitochondriální membrány patologie   MeSH
• mitochondrie fyziologie   patologie   MeSH
• nealkoholová steatóza jater etiologie   MeSH
• oxidační stres MeSH
• Parkinsonova nemoc etiologie   MeSH
• reperfuzní poškození myokardu farmakoterapie   MeSH
• Reyeův syndrom etiologie   MeSH
• salicylany toxicita   MeSH
• syndromy suchého oka etiologie   MeSH
• vápník chemie   metabolismus   MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

Acute streptozotocin diabetes mellitus (DM) as well as remote ischemic preconditioning (RPC) has shown a favorable effect on the postischemic-reperfusion function of the myocardium. Cardioprotective mechanisms offered by these experimental models involve the mitochondria with the changes in functional properties of membrane as the end-effector. The aim was to find out whether separate effects of RPC and DM would stimulate the mechanisms of cardioprotection to a maximal level or whether RPC and DM conditions would cooperate in stimulation of cardioprotection. Experiments were performed on male Wistar rats divided into groups: control, DM, RPC and DM treated by RPC (RPC+DM). RPC protocol of 3 cycles of 5-min hind limb ischemia followed by 5-min reperfusion was used. Ischemic-reperfusion injury was induced by 30-min ischemia followed by 40-min reperfusion of the hearts in Langendorff mode. Mitochondria were isolated by differential centrifugation, infarct size assessed by staining with 1 % 2,3,5-triphenyltetrazolium chloride, mitochondrial membrane fluidity with a fluorescent probe DPH, CoQ(9) and CoQ(10) with HPLC. Results revealed that RPC as well as DM decreased the infarct size and preserved mitochondrial function by increasing the mitochondrial membrane fluidity. Both used models separately offered a sufficient protection against ischemic-reperfusion injury without an additive effect of their combination.

• MeSH
• časové faktory MeSH
• experimentální diabetes mellitus chemicky indukované   metabolismus   patologie   MeSH
• fluidita membrány MeSH
• fyziologická adaptace MeSH
• infarkt myokardu metabolismus   patologie   prevence a kontrola   MeSH
• mitochondriální membrány patologie   MeSH
• modely nemocí na zvířatech MeSH
• myokard metabolismus   patologie   MeSH
• potkani Wistar MeSH
• preparace izolovaného srdce MeSH
• přivykání k ischémii metody   MeSH
• regionální krevní průtok MeSH
• reperfuzní poškození myokardu metabolismus   patologie   prevence a kontrola   MeSH
• srdeční mitochondrie metabolismus   patologie   MeSH
• streptozocin MeSH
• zadní končetina krevní zásobení   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Dimethyl sulfoxide (DMSO) is a widely used prototypical chemical inducer of cell differentiation. In the present study, the effects of DMSO on susceptibility of human myeloid leukemia U937 cells towards ligation of distinct death receptors (DRs) were investigated. DMSO sensitized cells towards induction of apoptosis by anti-Fas antibody, tumour necrosis factor-alpha or Apo2 ligand/TNF-related apoptosis-inducing ligand (TRAIL). Apart from increasing Fas levels, DMSO did not affect expression of proteins in death signal transduction, such as Bcl-2 family proteins, FADD, caspase-3 and -8, the inhibitor of apoptosis proteins (IAPs) or cFLIP(L). However, DMSO significantly potentiated mitochondrial membrane depolarization, suggesting that this mechanism might be involved in sensitisation of myeloid cells to DR-mediated apoptosis.

• MeSH
• adaptorové proteiny signální transdukční metabolismus   MeSH
• antigeny CD95 metabolismus   MeSH
• apoptóza účinky záření   MeSH
• dimethylsulfoxid farmakologie   MeSH
• financování organizované MeSH
• FLIP (buněčný) MeSH
• intracelulární signální peptidy a proteiny MeSH
• kaspasa 3 MeSH
• kaspasa 8 MeSH
• kaspasy metabolismus   MeSH
• kryoprotektivní látky farmakologie   MeSH
• lidé MeSH
• membránové glykoproteiny metabolismus   MeSH
• mitochondriální membrány metabolismus   patologie   MeSH
• mitochondrie metabolismus   patologie   MeSH
• myeloidní leukemie metabolismus   patologie   MeSH
• protein FADD asociující s Fas MeSH
• protein TRAIL MeSH
• proteiny regulující apoptózu metabolismus   MeSH
• protoonkogenní proteiny c-bcl-2 metabolismus   MeSH
• TNF-alfa metabolismus   MeSH
• U937 buňky MeSH
• Check Tag
• lidé MeSH