Multi-factorial mitochondrial damage exhibits a "vicious circle" that leads to a progression of mitochondrial dysfunction and multi-organ adverse effects. Mitochondrial impairments (mitochondriopathies) are associated with severe pathologies including but not restricted to cancers, cardiovascular diseases, and neurodegeneration. However, the type and level of cascading pathologies are highly individual. Consequently, patient stratification, risk assessment, and mitigating measures are instrumental for cost-effective individualized protection. Therefore, the paradigm shift from reactive to predictive, preventive, and personalized medicine (3PM) is unavoidable in advanced healthcare. Flavonoids demonstrate evident antioxidant and scavenging activity are of great therapeutic utility against mitochondrial damage and cascading pathologies. In the context of 3PM, this review focuses on preclinical and clinical research data evaluating the efficacy of flavonoids as a potent protector against mitochondriopathies and associated pathologies.

• MeSH
• antioxidancia farmakologie   terapeutické užití   MeSH
• cytoprotekce účinky léků   MeSH
• flavonoidy farmakologie   terapeutické užití   MeSH
• individualizovaná medicína metody   MeSH
• lidé MeSH
• mitochondriální nemoci diagnóza   prevence a kontrola   MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• mitofagie účinky léků   MeSH
• oxidační stres účinky léků   MeSH
• prognóza MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Kinetin (N6-furfuryladenine), a plant growth substance of the cytokinin family, has been shown to modulate aging and various age-related conditions in animal models. Here we report the synthesis of kinetin isosteres with the purine ring replaced by other bicyclic heterocycles, and the biological evaluation of their activity in several in vitro models related to neurodegenerative diseases. Our findings indicate that kinetin isosteres protect Friedreich́s ataxia patient-derived fibroblasts against glutathione depletion, protect neuron-like SH-SY5Y cells from glutamate-induced oxidative damage, and correct aberrant splicing of the ELP1 gene in fibroblasts derived from a familial dysautonomia patient. Although the mechanism of action of kinetin derivatives remains unclear, our data suggest that the cytoprotective activity of some purine isosteres is mediated by their ability to reduce oxidative stress. Further, the studies of permeation across artificial membrane and model gut and blood-brain barriers indicate that the compounds are orally available and can reach central nervous system. Overall, our data demonstrate that isosteric replacement of the kinetin purine scaffold is a fruitful strategy for improving known biological activities of kinetin and discovering novel therapeutic opportunities.

• MeSH
• cytoprotekce MeSH
• kinetin chemická syntéza   chemie   farmakologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• molekulární struktura MeSH
• oxidační stres účinky léků   MeSH
• puriny chemická syntéza   chemie   farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

ETHNOPHARMACOLOGICAL RELEVANCE: Macaranga Thou. (Euphorbiaceae) is a large genus that comprises over 300 species distributed between Western Africa and the islands of the South Pacific. Plants of this genus have a long-standing history of use in traditional medicine for different purposes, including the treatment of inflammation. Fresh and dried leaves of certain Macaranga species (e.g. M. tanarius (L.) Müll.Arg.), have been used to treat cuts, bruises, boils, swellings, sores and covering of wounds in general. Several reports described Macaranga spp. being a rich source of polyphenols, such as prenylated stilbenoids and flavonoids, mostly responsible for its biological activity. Similarly, an abundant content of prenylated stilbenes was also described in M. siamensis S.J.Davies, species recently identified (2001) in Thailand. While the respective biological activity of the prenylated stilbenes from M. siamensis was poorly investigated to date, our recent study pointed out the interest as the natural source of several novel anti-inflammatory stilbenoids isolated from this species. AIM OF THE STUDY: This work investigated the potential anti-inflammatory effects of the stilbenoid macasiamenene F (MF) isolated from M. siamensis S.J.Davies (Euphorbiaceae) on the lipopolysaccharide (LPS)-induced inflammation-like response of monocytes and microglia, major cells involved in the peripheral and central inflammatory response, respectively. MATERIALS AND METHODS: LPS-induced stimulation of TLR4 signaling led to the activation of inflammatory pathways in in vitro models of THP-1 and THP-1-XBlue™-MD2-CD14 human monocytes, BV-2 mouse microglia, and an ex vivo model of brain-sorted mouse microglia. The ability of the stilbenoid MF to intervene in the IкB/NF-кB and MAPKs/AP-1 inflammatory cascade was investigated. The gene and protein expressions of the pro-inflammatory cytokines IL-1β and TNF-α were evaluated at the transcription and translation levels. The protective effect of MF against LPS-triggered microglial loss was assessed by cell counting and the LDH assay. RESULTS: MF demonstrated beneficial effects, reducing both monocyte and microglial inflammation as assessed in vitro. It efficiently inhibited the degradation of IкBα, thereby reducing the NF-кB activity and TNF-α expression in human monocytes. Furthermore, the LPS-induced expression of IL-1β and TNF-α in microglia was dampened by pre-, co-, or post-treatment with MF. In addition to its anti-inflammatory effect, MF demonstrated a cytoprotective effect against the LPS-induced death of BV-2 microglia. CONCLUSION: Our research into anti-inflammatory and protective effects of MF has shown that it is a promising candidate for further in vitro and in vivo investigations of MF interventions with respect to acute and chronic inflammation, including potentially beneficial effects on the inflammatory component of brain diseases such as stroke and Alzheimer's disease.

• MeSH
• antiflogistika izolace a purifikace   farmakologie   terapeutické užití   MeSH
• cytoprotekce účinky léků   fyziologie   MeSH
• Euphorbiaceae * MeSH
• kultivované buňky MeSH
• lidé MeSH
• lipopolysacharidy toxicita   MeSH
• mediátory zánětu antagonisté a inhibitory   metabolismus   MeSH
• mikroglie účinky léků   metabolismus   MeSH
• monocyty účinky léků   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• prenylace účinky léků   fyziologie   MeSH
• rostlinné extrakty izolace a purifikace   farmakologie   terapeutické užití   MeSH
• stilbeny izolace a purifikace   farmakologie   terapeutické užití   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zánět farmakoterapie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The endothelial glycocalyx (GCX) coats all the vascular endothelium and plays the pivotal role in the microcirculation under physiological and pathological conditions. Alteration of GCX may play the key role in the critical illness associated microcirculatory dysfunction, promoting tissue hypoperfusion and contributing to organ failure. GCX integrity may be impaired by many factors, but focused human studies evaluating the effect of anesthesia, major surgery or common ICU interventions are scarce. GCX protection bears potential to limit organ damage. The aim of the project is to apply new technologies for bed-side assessment of GCX and to describe its relevance dynamics in critical illness and after major surgery. Major expected impact of the research is to bring vitally important data on factors affecting and/or modulating GCX integrity, to assess feasibility and reliability of measuring GCX in clinical practice in order to optimize treatment modalities with regard to protect the GCX.

Endoteliální glykokalyx (GCX) pokrývá povrch endoteliálních buněk v cévním systému, má významnou roli v regulaci mikrovaskulární homeostázy za fyziologických i patologických stavů. K alteraci GCX v kritických stavech dochází řadou mechanismů, výsledkem je ztráta bariérové funkce GCX. Porucha integrity GCX hraje významnou roli v rozvoji tkáňové hypoperfuze a orgánového selhání. Vliv většiny postupů orgánové podpory v rámci anestezie a intenzivní péče (nutriční podpora, metody mimotělní podpory/náhrady orgánových funkcí) na GCX není znám. Cílem projektu je zhodnocení klinické využitelnosti nových poznatků o změnách GCX během operačního traumatu, anestezie a intenzivní péče a získání prioritních poznatků o vlivu lipidomu a parenterální výživy na GCX pro vývoj a optimalizaci postupů nutriční podpory. Vytvoření zvířecího modelu na praseti by mělo dále otevřít možnosti testování nových postupů na ochranu GCX.

• MeSH
• cytoprotekce MeSH
• endoteliální buňky MeSH
• glykokalyx MeSH
• kritický stav MeSH
• lipidomika MeSH
• parenterální výživa MeSH
• peroperační doba MeSH
• peroperační komplikace MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• cytologie, klinická cytologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

In order to reduce tissue damage caused by ischemia-reperfusion injury, this study aims to investigate the protective effect and mechanism of ?-lipoic acid on hepatic ischemia-reperfusion injury in rats. The bloodstream of rats was blocked in the left middle and left lateral liver lobes of the liver. Forty rats were randomly divided into two groups: treatment group and injury group. Rats were injected with either 25 mg/1 ml of alpha-lipoic acid (treatment group) or 1 ml of saline (injury group) into the caudal vein 15 min before hepatic ischemia-reperfusion. Rat serum alanine aminotransferase (GPT), glutathione (GSH) and superoxide dismutase (SOD) levels were examined at various time points (1, 3, 6 and 12 h) in both groups. Changes in nuclear factor kappa B P65 (NF-kappaB P65) expression in ischemia-reperfusion liver at various time points after reperfusion (1, 3, 6 and 12 h) were evaluated through immunohistochemistry assay. Changes in macrophage inflammatory protein-2 (MIP-2) mRNA and inducible nitric oxide synthase (iNOS) mRNA expression in ischemic reperfused rat livers were detected by RT-PCR. Serum GPT level was significantly higher in the injury group than in the treatment group (P<0.01). NF-kappaB P65, MIP-2 mRNA and iNOS mRNA expression in ischemic reperfused rat livers were significantly higher in the injury group than in the treatment group (P<0.01). Serum GSH and SOD levels were higher in the treatment group than in the injury group (P<0.01). Alpha-lipoic acid significantly reduced ischemia-reperfusion injury in rat livers. This may be associated to the direct scavenging of oxygen-free radicals, increased GSH production, and the activation of downstream media due to decreased NF-kappaB and GSH consumption.

• MeSH
• chemokin CXCL2 genetika   metabolismus   MeSH
• cytoprotekce MeSH
• glutathion metabolismus   MeSH
• játra krevní zásobení   metabolismus   patologie   účinky léků   MeSH
• kyselina lipoová farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• nemoci jater genetika   metabolismus   patologie   prevence a kontrola   MeSH
• oxidační stres účinky léků   MeSH
• potkani Wistar MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• reperfuzní poškození genetika   metabolismus   patologie   prevence a kontrola   MeSH
• scavengery volných radikálů farmakologie   MeSH
• signální transdukce MeSH
• superoxiddismutasa metabolismus   MeSH
• synthasa oxidu dusnatého, typ II genetika   metabolismus   MeSH
• transkripční faktor RelA genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The exposure of naked unprotected skin to solar radiation may result in numerous acute and chronic undesirable effects. Evidence suggests that silymarin, a standardized extract from Silybum marianum (L.) Gaertn. seeds, and its major component silybin suppress UVB-induced skin damage. Here, we aimed to investigate the UVA-protective effects of silymarin's less abundant flavonolignans, specifically isosilybin (ISB), silychristin (SC), silydianin (SD), and 2,3-dehydrosilybin (DHSB). Normal human dermal fibroblasts (NHDF) pre-treated for 1 h with flavonolignans were then exposed to UVA light using a solar simulator. Their effects on reactive oxygen species (ROS), carbonylated proteins and glutathione (GSH) level, caspase-3 activity, single-strand breaks' (SSBs) formation and protein level of matrix metalloproteinase-1 (MMP-1), heme oxygenase-1 (HO-1), and heat shock protein (HSP70) were evaluated. The most pronounced preventative potential was found for DHSB, a minor component of silymarin, and SC, the second most abundant flavonolignan in silymarin. They had significant effects on most of the studied parameters. Meanwhile, a photoprotective effect of SC was mostly found at double the concentration of DHSB. ISB and SD protected against GSH depletion, the generation of ROS, carbonylated proteins and SSBs, and caspase-3 activation, but had no significant effect on MMP-1, HO-1, or HSP70. In summary, DHSB and to a lesser extent other silymarin flavonolignans are potent UVA-protective compounds. However, due to the in vitro phototoxic potential of DHSB published elsewhere, further studies are needed to exclude phototoxicity for humans as well as to confirm our results on human skin ex vivo and in vivo.

• MeSH
• cytoprotekce účinky léků   MeSH
• fibroblasty účinky léků   účinky záření   MeSH
• glutathion metabolismus   MeSH
• hemoxygenasa-1 metabolismus   MeSH
• jednořetězcové zlomy DNA účinky záření   MeSH
• karbonylace proteinů účinky záření   MeSH
• kaspasa 3 metabolismus   MeSH
• kultivované buňky MeSH
• kůže účinky záření   MeSH
• lidé MeSH
• matrixová metaloproteinasa 1 metabolismus   MeSH
• přípravky chránící proti slunci farmakologie   MeSH
• proteiny tepelného šoku HSP70 metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• silymarin analogy a deriváty   farmakologie   MeSH
• ultrafialové záření škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Decreased inflammatory status has been reported in subjects with mild unconjugated hyperbilirubinemia. However, mechanisms of the anti-inflammatory actions of bilirubin (BR) are not fully understood. The aim of this study is to assess the role of BR in systemic inflammation using hyperbilirubinemic Gunn rats as well as their normobilirubinemic littermates and further in primary hepatocytes. The rats were treated with lipopolysaccharide (LPS, 6 mg/kg intraperitoneally) for 12 h, their blood and liver were collected for analyses of inflammatory and hepatic injury markers. Primary hepatocytes were treated with BR and TNF-α. LPS-treated Gunn rats had a significantly decreased inflammatory response, as evidenced by the anti-inflammatory profile of white blood cell subsets, and lower hepatic and systemic expressions of IL-6, TNF-α, IL-1β, and IL-10. Hepatic mRNA expression of LPS-binding protein was upregulated in Gunn rats before and after LPS treatment. In addition, liver injury markers were lower in Gunn rats as compared to in LPS-treated controls. The exposure of primary hepatocytes to TNF-α with BR led to a milder decrease in phosphorylation of the NF-κB p65 subunit compared to in cells without BR. In conclusion, hyperbilirubinemia in Gunn rats is associated with an attenuated systemic inflammatory response and decreased liver damage upon exposure to LPS.

• MeSH
• apoptóza účinky léků   MeSH
• bilirubin farmakologie   MeSH
• biologické markery krev   MeSH
• cytokiny krev   genetika   metabolismus   MeSH
• cytoprotekce účinky léků   MeSH
• fosforylace účinky léků   MeSH
• hepatocyty metabolismus   MeSH
• hyperbilirubinemie krev   komplikace   MeSH
• játra metabolismus   MeSH
• kultivované buňky MeSH
• leukocyty metabolismus   MeSH
• lipopolysacharidy MeSH
• messenger RNA genetika   metabolismus   MeSH
• NF-kappa B metabolismus   MeSH
• potkani Gunn MeSH
• signální transdukce MeSH
• zánět komplikace   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Autophagy can regulate cell growth, proliferation, and stability of cell environment. Its dysfunction can be involved in a variety of diseases. Hydrogen sulfide (H(2)S) is an important signaling molecule that regulates many physiological and pathological processes. Recent studies indicate that H(2)S plays an important protective role in many diseases through influencing autophagy, but its mechanism is not fully understood. This article reviewed the progress about the effect of H(2)S on autophagy in diseases in recent years in order to provide theoretical basis for the further research on the interaction of H(2)S and autophagy and the mechanisms involved.

• MeSH
• autofagie fyziologie   MeSH
• cytoprotekce účinky léků   fyziologie   MeSH
• gasotransmitery metabolismus   MeSH
• ischemie farmakoterapie   metabolismus   MeSH
• lidé MeSH
• proliferace buněk účinky léků   fyziologie   MeSH
• sulfan aplikace a dávkování   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

We studied the role of the delta, micro, and kappa opioid receptor (OR) subtypes in the cardioprotective effect of chronic continuous normobaric hypoxia (CNH) in the model of acute anoxia-reoxygenation of isolated cardiomyocytes. Adaptation of rats to CNH was performed by their exposure to atmosphere containing 12 % of O(2) for 21 days. Anoxia-reoxygenation of cardiomyocytes isolated from normoxic control rats caused the death of 51 % of cells and lactate dehydrogenase (LDH) release. Adaptation of rats to CNH resulted in the anoxia/reoxygenation-induced cardiomyocyte death of only 38 %, and reduced the LDH release by 25 %. Pre-incubation of the cells with either the non-selective OR (opioid receptor) blocker naloxone (300 nM/l), the delta OR antagonist TIPP(psi) (30 nM/l), the selective delta(2) OR antagonist naltriben (1 nM/l) or the micro OR antagonist CTAP (100 nM/l) for 25 minutes before anoxia abolished the reduction of cell death and LDH release afforded by CNH. The antagonist of delta(1) OR BNTX (1 nM/l) or the kappa OR antagonist nor-binaltorphimine (3 nM/l) did not influence the cytoprotective effects of CNH. Taken together, the cytoprotective effect of CNH is associated with the activation of the delta(2) and micro OR localized on cardiomyocytes.

• MeSH
• cytoprotekce účinky léků   fyziologie   MeSH
• hypoxie metabolismus   MeSH
• kardiomyocyty účinky léků   metabolismus   MeSH
• krysa rodu rattus MeSH
• kultivované buňky MeSH
• mediátory zánětu antagonisté a inhibitory   metabolismus   MeSH
• náhodné rozdělení MeSH
• narkotika - antagonisté farmakologie   MeSH
• potkani Wistar MeSH
• receptory opiátové metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Heat Shock Protein 90 (HSP90) is a fertility-associated protein, the expression of which positively correlates with sperm quality in many species. Geranylgeranylacetone (GGA) is reported to induce expression of HSP90. The present study aimed to investigate whether GGA induced expression of HSP90 in Acipenser sinensis sperm to exert a cryoprotective effect. Sperm from five male A. sinensis was combined with extender containing 20 mmol/L tris pH = 8.1, 10% v/v methanol, 2-5 mmol/L KCl, 15 mmol/L lactose, and 15 mmol/L trehalose, with GGA at 0, 14, 67, 135, 673, 1346, or 6731 μmol/L. After cryopreservation and thawing, the percentage of motile spermatozoa, spermatozoon curvilinear velocity (VCL), straight-line velocity (VSL), average path velocity (VAP), acrosome integrity, and membrane integrity, as well as fertility were evaluated. Sperm quality increased with the increase of GGA to 673 μmol/L, but decreased at higher concentrations. Expression levels of HSP90α were detected by Western blot in sperm frozen with GGA at 673 μmol/L (highest obtained sperm quality), 6731 μmol/L (highest GGA concentration), and a control without GGA. The expression of HSP90α increased with the increase in GGA, with lowest expression observed in the control. GGA was found to induce increase of HSP90α, and this increase was associated with higher quality cryopreserved sperm at concentrations ≤673 μmol/L. This research suggests a viable technique to increase the quality of cryopreserved A. sinensis sperm by adding GGA to induce expression of HSP90α.

• MeSH
• cytoprotekce * účinky léků   genetika   MeSH
• diterpeny farmakologie   MeSH
• enzymová indukce účinky léků   MeSH
• kryoprezervace veterinární   MeSH
• kryoprotektivní látky metabolismus   farmakologie   MeSH
• motilita spermií genetika   MeSH
• proteiny tepelného šoku HSP90 genetika   metabolismus   MeSH
• ryby * genetika   metabolismus   MeSH
• spermie MeSH
• uchování spermatu * veterinární   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH