The crucial physiological process of heme breakdown yields biliverdin (BV) and bilirubin (BR) as byproducts. BV, BR, and the enzymes involved in their production (the "yellow players-YP") are increasingly documented as endogenous modulators of human health. Mildly elevated serum bilirubin concentration has been correlated with a reduced risk of multiple chronic pro-oxidant and pro-inflammatory diseases, especially in the elderly. BR and BV per se have been demonstrated to protect against neurodegenerative diseases, in which heme oxygenase (HMOX), the main enzyme in the production of pigments, is almost always altered. HMOX upregulation has been interpreted as a tentative defense against the ongoing pathologic mechanisms. With the demonstration that multiple cells possess YP, their propensity to be modulated, and their broad spectrum of activity on multiple signaling pathways, the YP have assumed the role of an adjustable system that can promote health in adults. Based on that, there is an ongoing effort to induce their activity as a therapeutic option, and natural compounds are an attractive alternative to the goal, possibly requiring only minimal changes in the life style. We review the most recent evidence of the potential of natural compounds in targeting the YP in the context of the most common pathologic condition of adult and elderly life.
Tick-borne encephalitis virus (TBEV), the causative agent of tick-borne encephalitis (TBE), is a medically important flavivirus endemic to the European-Asian continent. Although more than 12,000 clinical cases are reported annually worldwide, there is no anti-TBEV therapy available to treat patients with TBE. Porphyrins are macrocyclic molecules consisting of a planar tetrapyrrolic ring that can coordinate a metal cation. In this study, we investigated the cytotoxicity and anti-TBEV activity of a large series of alkyl- or (het)aryl-substituted porphyrins, metalloporphyrins, and chlorins and characterized their molecular interactions with the viral envelope in detail. Our structure-activity relationship study showed that the tetrapyrrole ring is an essential structural element for anti-TBEV activity, but that the presence of different structurally distinct side chains with different lengths, charges, and rigidity or metal cation coordination can significantly alter the antiviral potency of porphyrin scaffolds. Porphyrins were demonstrated to interact with the TBEV lipid membrane and envelope protein E, disrupt the TBEV envelope and inhibit the TBEV entry/fusion machinery. The crucial mechanism of the anti-TBEV activity of porphyrins is based on photosensitization and the formation of highly reactive singlet oxygen. In addition to blocking viral entry and fusion, porphyrins were also observed to interact with RNA oligonucleotides derived from TBEV genomic RNA, indicating that these compounds could target multiple viral/cellular structures. Furthermore, immunization of mice with porphyrin-inactivated TBEV resulted in the formation of TBEV-neutralizing antibodies and protected the mice from TBEV infection. Porphyrins can thus be used to inactivate TBEV while retaining the immunogenic properties of the virus and could be useful for producing new inactivated TBEV vaccines.
- MeSH
- antivirové látky farmakologie terapeutické užití MeSH
- internalizace viru MeSH
- kationty terapeutické užití MeSH
- klíšťová encefalitida * MeSH
- lidé MeSH
- myši MeSH
- porfyriny * farmakologie terapeutické užití MeSH
- protilátky virové terapeutické užití MeSH
- RNA MeSH
- virový obal MeSH
- viry klíšťové encefalitidy * genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Anionic cyclopentadienyl (Cp) and its pentamethyl-substituted derivative (Cp*) serve as crucial ligands for creating stable π-coordinated materials, including catalysts. From a structural perspective, the π-extended analog of Cp, known as an N-fused porphyrin (NFP), is recognized as an intriguing 18π aromatic chromophore, offering near-infrared (NIR) optical properties that can be fine-tuned through metal complexation. When coordinated with rhodium at the central NFP core, it forms a sandwich binuclear rhodium(III) complex along with terminal and bridging chloride ligands, denoted as Rh-1, and its bromo derivative, Rh-1-Br. In contrast to the bis-NFP complex of iron(II) reported previously by our team, both Rh-1 and Rh-1-Br complexes exhibit strong NIR optical properties and narrow HOMO-LUMO energy gaps, attributed to minimal orbital interactions between the two co-facial NFP ligands. Leveraging these NIR absorption properties, we assessed the photothermal conversion properties of Rh-1 and ligand 1, revealing high conversion efficiency. This suggests their potential application as photothermal agents for use in photothermal therapy.
Hydrogen/deuterium exchange (HDX) is a well-established analytical technique that enables monitoring of protein dynamics and interactions by probing the isotope exchange of backbone amides. It has virtually no limitations in terms of protein size, flexibility, or reaction conditions and can thus be performed in solution at different pH values and temperatures under controlled redox conditions. Thanks to its coupling with mass spectrometry (MS), it is also straightforward to perform and has relatively high throughput, making it an excellent complement to the high-resolution methods of structural biology. Given the recent expansion of artificial intelligence-aided protein structure modeling, there is considerable demand for techniques allowing fast and unambiguous validation of in silico predictions; HDX-MS is well-placed to meet this demand. Here we present a protocol for HDX-MS and illustrate its use in characterizing the dynamics and structural changes of a dimeric heme-containing oxygen sensor protein as it responds to changes in its coordination and redox state. This allowed us to propose a mechanism by which the signal (oxygen binding to the heme iron in the sensing domain) is transduced to the protein's functional domain.
The nonradioactive method, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) in the presence of Phos-tag (Phos-tag electrophoresis), is used to evaluate a kinase autophosphorylation and/or phosphotransfer reaction from a kinase/ATP to its protein substrate. This method outperforms radioisotope methods using [32P]ATP for detecting trace amounts of phosphorylated protein in fresh protein preparations. Phos-tag electrophoresis has been used to perform detailed analyses of the kinase activity of a heme-based oxygen sensor-specifically, a globin-coupled histidine kinase from the soil bacterium Anaeromyxobacter sp. Fw109-5 (AfGcHK).
Genomes of ticks display reductions, to various extents, in genetic coding for enzymes of the haem biosynthetic pathway. Here, we mined available transcriptomes of soft tick species and identified transcripts encoding only half of the enzymes involved in haem biosynthesis. Transcripts identified across most species examined were those coding for porphobilinogen synthase, coproporphyrinogen oxidase, protoporphyrinogen oxidase, and ferrochelatase. Genomic retention of porphobilinogen synthase seems to be soft tick-restricted as no such homologue has been identified in any hard tick species. Bioinformatic mining is thus strongly indicative of the lack of biochemical capacity for de novo haem biosynthesis, suggesting a requirement for dietary haem. In the hard tick Ixodes ricinus, depletion of dietary haem, i.e. serum feeding, leads to oviposition of haem-free eggs, with no apparent embryogenesis and larvae formation. In this work, we show that serum-fed Ornithodoros moubata females, unlike those of I. ricinus, laid haem-containing eggs similarly to blood-fed controls, but only by a small proportion of the serum-fed females. To enhance the effect of dietary haem depletion, O. moubata ticks were serum-fed consecutively as last nymphal instars and females. These females laid eggs with profoundly reduced haem deposits, confirming the host origin of the haem. These data confirm the ability of soft ticks to take up and allocate host haem to their eggs in order to drive reproduction of the ticks.
- MeSH
- Argasidae * MeSH
- hem MeSH
- Ixodidae * MeSH
- Ornithodoros * MeSH
- porfobilinogensynthasa MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The strong antifungal effect of sulfonated polystyrene nanoparticles (NPs) with an encapsulated tetraphenylporphyrin (TPP) photosensitizer is reported here. TPP is activated by visible light, resulting in the generation of singlet oxygen. Its antifungal action is potentiated in the presence of potassium iodide, yielding I2/I3−, another antifungal species. The NPs exhibit no dark toxicity, but a broad spectrum of antifungal photodynamic effects. The efficiency of this rapid killing (on the order of minutes) depends on the concentration of TPP NPs, potassium iodide, yeast species and temperature. A strong antifungal activity of TPP NPs is demonstrated on eleven pathogenic and opportunistic pathogenic yeast species (six Candida species and other yeast species, including melanized Hortaea werneckii). The composition and architecture of yeast cell envelope structures clearly influence the efficacy of photodynamic therapy. Candida krusei is the most sensitive to photodynamic therapy. Despite expectations, melanin does not provide Hortaea cells with marked resistance compared to white yeast species. The kinetics of the interaction of NPs with yeast cells is also described. This study may inspire and promote the fabrication of a new type of antiseptic for various skin injuries in clinical medicine.
Human serum albumin (HSA) is the most abundant plasma protein in circulation. The three most important drug-binding sites on HSA are Sudlow's Site I (subdomain IIA), Sudlow's Site II (subdomain IIIA), and Heme site (subdomain IB). Heme site and Site I are allosterically coupled; therefore, their ligands may be able to allosterically modulate the binding affinity of each other. In this study, the effects of four Heme site ligands (bilirubin, biliverdin, hemin, and methyl orange) on the interaction of the Site I ligand warfarin with HSA were tested, employing fluorescence spectroscopic, ultrafiltration, and ultracentrifugation studies. Our major results/conclusions are the following. (1) Quenching studies indicated no relevant interaction, while the other fluorescent model used suggested that each Heme site ligand strongly decreases the albumin binding of warfarin. (2) Ultrafiltration and ultracentrifugation studies demonstrated the complex modulation of warfarin-HSA interaction by the different Heme site markers; for example, bilirubin strongly decreased while methyl orange considerably increased the bound fraction of warfarin. (3) Fluorescence spectroscopic studies showed misleading results in these diligand-albumin interactions. (4) Different Heme site ligands can increase or decrease the albumin binding of warfarin and the outcome can even be concentration dependent (e.g., biliverdin and hemin).
- MeSH
- bilirubin MeSH
- biliverdin * MeSH
- hem metabolismus MeSH
- hemin MeSH
- lidé MeSH
- ligandy MeSH
- sérový albumin metabolismus MeSH
- warfarin * farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
3 strany : ilustrace ; 27 cm
Leták se zaměřuje na potravní doplňky obsahující hemové železo, které se používají k léčbě nedostatku železa
- MeSH
- deficit železa farmakoterapie MeSH
- dietní železo terapeutické užití MeSH
- hem MeSH
- potravní doplňky MeSH
- Publikační typ
- letáky MeSH
- Konspekt
- Farmacie. Farmakologie
- NLK Obory
- farmacie a farmakologie
- farmakoterapie
- vnitřní lékařství
Nedostatek železa je v populaci častým a zároveň však podceňovaným stavem. Jeho korelátem není zdaleka jen sideropenická anemie, ale vzhledem k pestrosti zapojení tohoto prvku v celé řadě biochemických reakcí lze očekávat i řadu dalších možných klinických projevů. Často nezbytná je pak vhodně zvolená suplementace perorálními přípravky. Zde bychom měli pečlivě zvažovat možný poměr očekávaného přínosu a potenciálních rizik spočívajících v nežádoucích účincích, případně interakci se složkami stravy či současně užívanými léky. Dostupné přípravky si nejsou rovnocenné – liší se nejen atomárně odlišným množstvím železa, ale především ve formě, která je určující pro způsob, jakým bude železo vstřebáváno. To v konečném důsledku definuje i rychlost úpravy deplece a snášenlivost konkrétního přípravku.
Iron deficiency is a common but underestimated condition in the population. Its correlate is far from only sideropenic anemia, but is due to the variety of involvement of this element in a number of biochemical reactions; several other possible clinical manifestations can be expected. Appropriately selected oral supplementation is often necessary. Here, we should carefully consider the possible ratio of expected benefits and potential risks of side effects, or interaction with dietary components or concomitant medications. The available preparations are not equivalent; they differ not only in atomically different amounts of iron but also, above all, in the form that determines the way in which the iron will be absorbed. This ultimately defines the rate of adjustment for depletion and the tolerability of a particular product.
