The study has been designed to characterize protein systems involved in the responses of rat hearts to chronic doxorubicin (DOX) treatment. We investigated the influence of DOX on cardiac function, mitogen-activated protein kinases (MAPKs) and heat stress proteins (HSPs). Doxorubicin was administered to rats by intraperitoneal injections over a period of 6 weeks. In control and DOX-treated hearts exposed to 20 min global ischemia and 40 min reperfusion the recovery of contractile function after ischemia/reperfusion (I/R) was determined. The levels and phosphorylation state of proteins in tissue samples were analyzed using specific antibodies. We found an activation of extracellular signal-regulated kinases (ERKs) in rat hearts exposed to DOX treatment and better recovery of contractile function after I/R. Analysis of HSPs showed that DOX induced up-regulation of the levels of HSP60 and down-regulation of HSP70 levels. The levels and/or specific phosphorylation of other studied proteins (p38-MAPK, HSP27, HSP90) were not influenced by DOX. The results point to the possible role of ERKs and some HSPs in mechanisms underlying the response of rat hearts to chronic DOX treatment.

• MeSH
• chaperon hsp60 metabolismus   MeSH
• doxorubicin MeSH
• extracelulárním signálem regulované MAP kinasy metabolismus   MeSH
• fosforylace MeSH
• kontrakce myokardu MeSH
• krysa rodu rattus MeSH
• mitogenem aktivované proteinkinasy p38 metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• myokard enzymologie   MeSH
• nádorové proteiny metabolismus   MeSH
• nemoci srdce chemicky indukované   enzymologie   patofyziologie   MeSH
• proteiny tepelného šoku HSP27 MeSH
• proteiny tepelného šoku HSP70 metabolismus   MeSH
• proteiny tepelného šoku HSP90 metabolismus   MeSH
• proteiny teplotního šoku metabolismus   MeSH
• protinádorová antibiotika MeSH
• reperfuzní poškození myokardu enzymologie   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• chrom toxicita   MeSH
• chromozomy fyziologie   ultrastruktura   MeSH
• Diptera fyziologie   účinky léků   MeSH
• mapování chromozomů MeSH
• proteiny tepelného šoku HSP70 analýza   fyziologie   MeSH
• reakce na tepelný šok fyziologie   účinky léků   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH

Stomatal ontogenesis, patterning, and function are hallmarks of environmental plant adaptation, especially to conditions limiting plant growth, such as elevated temperatures and reduced water availability. The specification and distribution of a stomatal cell lineage and its terminal differentiation into guard cells require a master regulatory protein phosphorylation cascade involving the YODA mitogen-activated protein kinase kinase kinase. YODA signaling results in the activation of MITOGEN-ACTIVATED PROTEIN KINASEs (MPK3 and MPK6), which regulate transcription factors, including SPEECHLESS (SPCH). Here, we report that acute heat stress affects the phosphorylation and deactivation of SPCH and modulates stomatal density. By using complementary molecular, genetic, biochemical, and cell biology approaches, we provide solid evidence that HEAT SHOCK PROTEINS 90 (HSP90s) play a crucial role in transducing heat-stress response through the YODA cascade. Genetic studies revealed that YODA and HSP90.1 are epistatic, and they likely function linearly in the same developmental pathway regulating stomata formation. HSP90s interact with YODA, affect its cellular polarization, and modulate the phosphorylation of downstream targets, such as MPK6 and SPCH, under both normal and heat-stress conditions. Thus, HSP90-mediated specification and differentiation of the stomatal cell lineage couples stomatal development to environmental cues, providing an adaptive heat stress response mechanism in plants.

• MeSH
• Arabidopsis fyziologie   MeSH
• buněčná diferenciace MeSH
• buněčné dělení MeSH
• buněčný rodokmen MeSH
• epigeneze genetická MeSH
• fosforylace MeSH
• kotyledon cytologie   MeSH
• MAP kinasy kinas (kinas) genetika   metabolismus   MeSH
• mitogenem aktivované proteinkinasy kinas metabolismus   MeSH
• mitogenem aktivované proteinkinasy metabolismus   MeSH
• mutace MeSH
• proteiny huseníčku genetika   metabolismus   MeSH
• proteiny tepelného šoku HSP90 genetika   metabolismus   MeSH
• průduchy rostlin cytologie   růst a vývoj   metabolismus   MeSH
• reakce na tepelný šok * MeSH
• regulace genové exprese u rostlin MeSH
• signální transdukce MeSH
• transkripční faktory bHLH metabolismus   MeSH
• vazba proteinů MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Publikace si klade za cíl, jako první dílo na trhu, komplexně postihnout a popsat aspekty i principy webové kartografie.; Publikace si klade za cíl, jako první dílo na trhu, komplexně postihnout a popsat aspekty i principy webové kartografie. První čistě teoretická část přináší jednoznačné vymezení pojmů a uvedení čtenáře do kontextu. Druhá část publikace popisuje jednotlivé aspekty webové kartografie, včetně pilířů pro vlastní tvorbu mapových aplikací: data a knihovny. Publikace je koncipována jako soubor pravidel, zásad, doporučení a metod pro autory webových map. Čtenář této monografie by se po jejím prostudování měl jednoznačně orientovat v aspektech a principech webové kartografie, správně pojmenovat dané termíny, a v neposlední řadě by měl pochopit proces tvorby webové mapy s veškerými kartografickými náležitostmi.

• MeSH
• cévní rezistence MeSH
• hypertenze MeSH
• nízká teplota MeSH
• termografie MeSH

BACKGROUND: Heat and cold are established environmental risk factors for human health. However, mapping the related health burden is a difficult task due to the complexity of the associations and the differences in vulnerability and demographic distributions. In this study, we did a comprehensive mortality impact assessment due to heat and cold in European urban areas, considering geographical differences and age-specific risks. METHODS: We included urban areas across Europe between Jan 1, 2000, and Dec 12, 2019, using the Urban Audit dataset of Eurostat and adults aged 20 years and older living in these areas. Data were extracted from Eurostat, the Multi-country Multi-city Collaborative Research Network, Moderate Resolution Imaging Spectroradiometer, and Copernicus. We applied a three-stage method to estimate risks of temperature continuously across the age and space dimensions, identifying patterns of vulnerability on the basis of city-specific characteristics and demographic structures. These risks were used to derive minimum mortality temperatures and related percentiles and raw and standardised excess mortality rates for heat and cold aggregated at various geographical levels. FINDINGS: Across the 854 urban areas in Europe, we estimated an annual excess of 203 620 (empirical 95% CI 180 882-224 613) deaths attributed to cold and 20 173 (17 261-22 934) attributed to heat. These corresponded to age-standardised rates of 129 (empirical 95% CI 114-142) and 13 (11-14) deaths per 100 000 person-years. Results differed across Europe and age groups, with the highest effects in eastern European cities for both cold and heat. INTERPRETATION: Maps of mortality risks and excess deaths indicate geographical differences, such as a north-south gradient and increased vulnerability in eastern Europe, as well as local variations due to urban characteristics. The modelling framework and results are crucial for the design of national and local health and climate policies and for projecting the effects of cold and heat under future climatic and socioeconomic scenarios. FUNDING: Medical Research Council of UK, the Natural Environment Research Council UK, the EU's Horizon 2020, and the EU's Joint Research Center.

• MeSH
• dospělí MeSH
• hodnocení vlivů na zdraví * MeSH
• lidé MeSH
• nízká teplota * MeSH
• velkoměsta MeSH
• vysoká teplota * MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH
• velkoměsta MeSH

Cellular senescence leads to decreased tissue regeneration and inflammation and is associated with diabetes, neurodegenerative diseases, and tumorigenesis. However, the mechanisms of cellular senescence are not fully understood. Emerging evidence has indicated that c-Jun N-terminal kinase (JNK) signaling is involved in the regulation of cellular senescence. JNK can downregulate hypoxia inducible factor-1α to accelerate hypoxia-induced neuronal cell senescence. The activation of JNK inhibits mTOR activity and triggers autophagy, which promotes cellular senescence. JNK can upregulate the expression of p53 and Bcl-2 and accelerates cancer cell senescence; however, this signaling also mediates the expression of amphiregulin and PD-LI to achieve cancer cell immune evasion and prevents their senescence. The activation of JNK further triggers forkhead box O expression and its target gene Jafrac1 to extend the lifespan of Drosophila. JNK can also upregulate the expression of DNA repair protein poly ADP-ribose polymerase 1 and heat shock protein to delay cellular senescence. This review discusses recent advances in understanding the function of JNK signaling in cellular senescence and includes a comprehensive analysis of the molecular mechanisms underlying JNK-mediated senescence evasion and oncogene-induced cellular senescence. We also summarize the research progress in anti-aging agents that target JNK signaling. This study will contribute to a better understanding of the molecular targets of cellular senescence and provides insights into anti-aging, which may be used to develop drugs for the treatment of aging-related diseases.

• MeSH
• hypoxie MeSH
• JNK mitogenem aktivované proteinkinasy * metabolismus   MeSH
• lidé MeSH
• MAP kinasový signální systém MeSH
• signální transdukce * MeSH
• stárnutí buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

• MeSH
• novorozenec MeSH
• termografie MeSH
• vysoká teplota MeSH
• Check Tag
• novorozenec MeSH

BRAFV600E mutations occur in ∼10% of colorectal cancer cases, are associated with poor survival, and have limited responses to BRAF/MEK inhibition with or without EGFR inhibition. There is an unmet need to understand the biology of poor prognostic BRAFMT colorectal cancer. We have used differential gene expression and pathway analyses of untreated stage II and stage III BRAFMT (discovery set: n = 31; validation set: n = 26) colorectal cancer, and an siRNA screen to characterize the biology underpinning the BRAFMT subgroup with poorest outcome. These analyses identified the unfolded protein response (UPR) as a novel and druggable pathway associated with the BRAFMT colorectal cancer subgroup with poorest outcome. We also found that oncogenic BRAF drives endoplasmic reticulum (ER) stress and UPR pathway activation through MEK/ERK. Furthermore, inhibition of GRP78, the master regulator of the UPR, using siRNA or small molecule inhibition, resulted in acute ER stress and apoptosis, in particular in BRAFMT colorectal cancer cells. In addition, dual targeting of protein degradation using combined Carfilzomib (proteasome inhibitor) and ACY-1215 (HDAC6-selective inhibitor) treatment resulted in marked accumulation of protein aggregates, acute ER stress, apoptosis, and therapeutic efficacy in BRAFMT in vitro and xenograft models. Mechanistically, we found that the apoptosis following combined Carfilzomib/ACY-1215 treatment is mediated through increased CHOP expression. Taken together, our findings indicate that oncogenic BRAF induces chronic ER stress and that inducers of acute ER stress could be a novel treatment strategy for poor prognostic BRAFMT colorectal cancer. Mol Cancer Ther; 17(6); 1280-90. ©2018 AACR.

• MeSH
• apoptóza účinky léků   genetika   MeSH
• biologické modely MeSH
• inhibitory proteinkinas farmakologie   MeSH
• kolorektální nádory farmakoterapie   genetika   metabolismus   mortalita   MeSH
• kyseliny hydroxamové farmakologie   MeSH
• lidé MeSH
• MAP kinasový signální systém MeSH
• mutace * MeSH
• nádorové biomarkery MeSH
• nádorové buněčné linie MeSH
• oligopeptidy farmakologie   MeSH
• prognóza MeSH
• proteiny teplotního šoku genetika   metabolismus   MeSH
• proteosyntéza MeSH
• protinádorové látky farmakologie   MeSH
• protoonkogenní proteiny B-raf antagonisté a inhibitory   genetika   metabolismus   MeSH
• pyrimidiny farmakologie   MeSH
• signální dráha UPR účinky léků   MeSH
• signální transdukce účinky léků   MeSH
• stres endoplazmatického retikula účinky léků   genetika   MeSH
• transkripční faktor CHOP genetika   metabolismus   MeSH
• viabilita buněk účinky léků   genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Insect adipokinetic hormones (AKHs) are pleiotropic hormones known to play a protective role in response to oxidative stress (OS). However, the precise signaling pathways are unclear. We present evidence that AKH may primarily employ the Forkhead box class O transcription factor (FoxO) to exert this effect. The impact of knocking down AKH synthesis or its over-expression in its response to OS was studied in Drosophila melanogaster. AKH knockdown (AKH-RNAi) as well as AKH overexpression (AKH-oex) was achieved using the Gal-4/UAS system and controls were w(1118) (+/+), AKH-Gal4/+, UAS-AKH/+ and UAS-AKH-RNAi/+. Exposure to 80 μM hydrogen peroxide (HP) revealed that AKH-RNAi flies showed significantly higher mortality than AKH-oex or the respective control lines. This susceptibility was evidenced by significantly enhanced levels of protein carbonyls - a biomarker of OS, in AKH-RNAi flies compared to controls and AKH-oex flies. Interestingly, AKH-oex flies had the least amount of protein carbonyls. AKH-RNAi flies had significantly less dFoxO transcript and translated protein compared to control and AKH-oex flies in un-challenged condition as well as when challenged with HP. Sestrin - a major antioxidant defense protein and one of the targets of dFoxO - was also significantly down-regulated (both at mRNA and protein level) in AKH-RNAi flies (both unchallenged and challenged with HP) compared to control flies and flies with over-expressed AKH. These findings imply that dFoxO may act downstream of AKH as a transcription factor to mediate response to OS in D. melanogaster.

• MeSH
• biologické markery metabolismus   MeSH
• Drosophila melanogaster genetika   fyziologie   MeSH
• forkhead transkripční faktory genetika   metabolismus   MeSH
• geneticky modifikovaná zvířata MeSH
• hmyzí hormony antagonisté a inhibitory   genetika   metabolismus   MeSH
• karbonylace proteinů účinky léků   MeSH
• křížení genetické MeSH
• kyselina pyrrolidonkarboxylová analogy a deriváty   antagonisté a inhibitory   metabolismus   MeSH
• léková rezistence MeSH
• MAP kinasový signální systém účinky léků   MeSH
• messenger RNA metabolismus   MeSH
• oligopeptidy antagonisté a inhibitory   genetika   metabolismus   MeSH
• oxidační stres * MeSH
• oxidancia toxicita   MeSH
• peroxid vodíku toxicita   MeSH
• proteiny Drosophily antagonisté a inhibitory   genetika   metabolismus   MeSH
• proteiny teplotního šoku genetika   metabolismus   MeSH
• regulace genové exprese * účinky léků   MeSH
• rekombinantní proteiny chemie   metabolismus   MeSH
• RNA interference MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH