ASK1-p38-NR4A2 Axis in H2O2-induced Necrosis

Background: The molecular mechanisms of p38 MAPK-mediated necrosis currently have not been well elucidated. Results: During oxidative stress, NR4A2 is phosphorylated and translocated into the cytosol in an ASK1-p38-dependent manner, which ultimately leads to the promotion of necrosis. Conclusion: ASK1-p38 MAPK pathway-dependent phosphorylation and subsequent cytoplasmic translocation of NR4A2 promote oxidative stress-induced necrosis. Significance: We found a novel intracellular signaling pathway that regulates oxidative stress-induced and p38-mediated necrosis.p38 mitogen-activated protein kinases (MAPKs) play important roles in various cellular stress responses, including cell death, which is roughly categorized into apoptosis and necrosis. Although p38 signaling has been extensively studied, the molecular mechanisms of p38-mediated cell death are unclear. ASK1 is a stress-responsive MAP3K that acts as an upstream kinase of p38 and is activated by various stresses, such as oxidative stress. Here, we show that NR4A2, a member of the NR4A nuclear receptor family, acts as a necrosis promoter downstream of ASK1-p38 pathway during oxidative stress. Although NR4A2 is well known as a nucleus-localized transcription factor, we found that it is translocated into the cytosol after phosphorylation by p38. Because the phosphorylation site mutants of NR4A2 cannot rescue the cell death-promoting activity, ASK1-p38 pathway-dependent phosphorylation and subsequent cytoplasmic translocation of NR4A2 may be required for oxidative stress-induced cell death. In addition, NR4A2-mediated cell death does not depend on caspases and receptor-interacting protein 1 (RIP1)-RIP3 complex, suggesting that NR4A2 promotes an RIP kinase-independent necrotic type of cell death. Our findings may enable a more precise understanding of molecular mechanisms that regulate oxidative stress-induced and p38-mediated necrosis

Monivammapotilaan kivunhoito

Tämän opinnäytetyön tarkoituksena oli kartoittaa monivammapotilaan kivunhoitoa ennen sairaalaan tuloa, sairaalassa ja kotona systemaattista kirjallisuuskatsausta soveltaen. Tavoitteena on edistää monivammapotilaan kivunhoitoa. Opinnäytetyöhön valikoitui analysoitavaksi 38 (=n) julkaisua. Monivammapotilaan kivunhoito vaatii moniammatillista osaamista ja yhteistyötä. Kivunhoidon oleellisena osana on kivun arviointi. Kipua voidaan arvioida erilaisin mittarein, kuten sanallinen asteikko (VRS), numeroasteikko (NRS) ja visuaalianalogiasteikko (VAS). Potilaan ollessa tajuton, kivunarviointi muuttuu haasteellisemmaksi, sillä silloin mittareita ei voida käyttää. Monivammapotilaan kipua hoidetaan pääsääntöisesti lääkkeillä. Keskeisimpiä lääkkeitä ovat tulehduskipulääkkeet, parasetamoli ja opioidit. Lääkkeettömiä kivunhoitomuotoja kuten asentohoito, fysikaaliset hoitomuodot, hengitysharjoitukset, musiikin kuuntelu, rentoutumis- ja mielikuvaharjoitukset, käytetään myös, mutta ne ovat tehokkaampia yhdistettynä lääkkeelliseen kivunhoitoon. Lääkehoito koostuu monen lääkeryhmän yhdistelmistä eli multimodaalisesta kivunhoidosta. Puudutteet ovat keskeinen osa monivammapotilaan kivunhoitoa, sillä ne vähentävät huomattavasti opioidien käyttöä. Kivunhoito on tasapainoilua potilaan kivuttomuuden ja kivunhoidon haittavaikutuksien välillä. Potilaan kivunhoito jatkuu koko hoidon ajan, myös kotiutumisen jälkeen. Kivunhoito on potilaan oikeus eikä ole olemassa mitään pätevää syytä jättää kipua hoitamatta. Monivammapotilaat ovat todella kivuliaita, joten kivun hoidon tutkiminen ja kehittäminen on tärkeää. Tehokkaalla kivunhoidolla voidaan ehkäistä kivun kroonistumista.The purpose of this thesis is to improve multi-trauma patients pain management before coming to a hospital, in hospital and at home by using a systematic literature review. The aim is to improve multi-trauma patient’s pain management. There was 38(=n) publications chosen for this thesis. The pain management of a multi-trauma patient requires multi-professional expertise and cooperation. An essential part of pain management is assessment of pain. The pain can be assessed with different kind of rating scales for example verbal rating scale (VRS), numeric rating scale (NRS) and visual analog scale (VAS). When patient is being unconscious assessment of pain becomes challenging so the rating scales cannot be used. The pain of a multi-trauma patient is mainly managed with medicine. The most common medicines are inflammatory drugs, paracetamol and opioids. Drug-free pain management formats such as position management, physical therapies, breathing exercises, listening to music, relaxing and imagination exercises are used but they are more effective combined with medicinal pain management. Medication consist of the combination of different drug groups called multimodal pain management. Regional anesthetics are a key part of the pain management of a multi-trauma patient because regional anesthetics reduce remarkably the use of opioids. Pain management is balancing between painless and side effects pain management. The pain management of the patient goes through the whole care also after discharging from hospital. Pain management is the patients right and there is no competent reason to not treat the pain. Multi-trauma patients are in a high amount of pain so the study and development of pain management is really important. With efficient pain management you can anticipate chronical pain

Terahertz diagnostic systems based on frequency combs without moving parts

We exploit information and communications tech-nologies to build a radio frequency-driven frequency comb spanning several hundred gigahertz. We investigated electro-optic modulators, which can serve as building blocks in frequency combs, terahertz generation and terahertz detection systems. These devices have high potential for applications in robust laser-based diagnostics at electron accelerators. During the last year, we have reduced the pulse length generated by a frequency-comb without moving parts by more than one order of magnitude to less than 150 fs, fitting a Lorentzian-type autocorrelation function

Filled skutterudite structure of europium ruthenium polyphosphide, EuRu4P12

The crystal structure of EuRu4P12 is isotypic with filled skutterudite structures of rare earth transition metal poly­phosphides: RFe4P12 (R = Ce, Pr, Nd, Sm and Eu), RRu4P12 (R = La, Ce, Pr and Nd) and ROs4P12 (R = La, Ce, Pr and Nd). The Ru cation is coordinated by six P anions in a distorted octa­hedral manner. The partially occupied Eu position (site occupancy 0.97) is enclosed by a cage formed by the corner-shared framework of the eight RuP6 octa­hedra

Neuroprotective effect of 5-aminolevulinic acid against low inorganic phosphate in neuroblastoma SH-SY5Y cells

PiT-1 (encoded by SLC20A1) and PiT-2 (encoded by SLC20A2) are type-III sodium-dependent phosphate cotransporters (NaPiTs). Recently, SLC20A2 mutations have been found in patients with idiopathic basal ganglia calcification (IBGC), and were predicted to bring about an inability to transport Pi from the extracellular environment. Here we investigated the effect of low Pi loading on the human neuroblastoma SH-SY5Y and the human glioblastoma A172 cell lines. The results show a different sensitivity to low Pi loading and differential regulation of type-III NaPiTs in these cells. We also examined whether 5-aminolevulinic acid (5-ALA) inhibited low Pi loading-induced neurotoxicity in SH-SY5Y cells. Concomitant application of 5-ALA with low Pi loading markedly attenuated low Pi-induced cell death and mitochondrial dysfunction via the induction of HO-1 by p38 MAPK. The findings provide us with novel viewpoints to understand the pathophysiology of IBGC, and give a new insight into the clinical prevention and treatment of IBGC

Regulation of NR4A nuclear receptors by p38

In Drosophila, the melanization reaction is an important defense mechanism against injury and invasion of microorganisms. Drosophila tyrosine hydroxylase (TH, also known as Pale) and dopa decarboxylase (Ddc), key enzymes in the dopamine synthesis pathway, underlie the melanin synthesis by providing the melanin precursors dopa and dopamine, respectively. It has been shown that expression of Drosophila TH and Ddc is induced in various physiological and pathological conditions, including bacterial challenge; however, the mechanism involved has not been fully elucidated. Here, we show that ectopic activation of p38 MAPK induces TH and Ddc expression, leading to upregulation of melanization in the Drosophila cuticle. This p38-dependent melanization was attenuated by knockdown of TH and Ddc, as well as by that of Drosophila HR38, a member of the NR4A family of nuclear receptors. In mammalian cells, p38 phosphorylated mammalian NR4As and Drosophila HR38 and potentiated these NR4As to transactivate a promoter containing NR4A-binding elements, with this transactivation being, at least in part, dependent on the phosphorylation. This suggests an evolutionarily conserved role for p38 MAPKs in the regulation of NR4As. Thus, p38-regulated gene induction through NR4As appears to function in the dopamine synthesis pathway and may be involved in immune and stress responses

Two distinct regions in Staphylococcus aureus GatCAB guarantee accurate tRNA recognition

In many prokaryotes the biosynthesis of the amide aminoacyl-tRNAs, Gln-tRNAGln and Asn-tRNAAsn, proceeds by an indirect route in which mischarged Glu-tRNAGln or Asp-tRNAAsn is amidated to the correct aminoacyl-tRNA catalyzed by a tRNA-dependent amidotransferase (AdT). Two types of AdTs exist: bacteria, archaea and organelles possess heterotrimeric GatCAB, while heterodimeric GatDE occurs exclusively in archaea. Bacterial GatCAB and GatDE recognize the first base pair of the acceptor stem and the D-loop of their tRNA substrates, while archaeal GatCAB recognizes the tertiary core of the tRNA, but not the first base pair. Here, we present the crystal structure of the full-length Staphylococcus aureus GatCAB. Its GatB tail domain possesses a conserved Lys rich motif that is situated close to the variable loop in a GatCAB:tRNAGln docking model. This motif is also conserved in the tail domain of archaeal GatCAB, suggesting this basic region may recognize the tRNA variable loop to discriminate Asp-tRNAAsn from Asp-tRNAAsp in archaea. Furthermore, we identified a 310 turn in GatB that permits the bacterial GatCAB to distinguish a U1–A72 base pair from a G1–C72 pair; the absence of this element in archaeal GatCAB enables the latter enzyme to recognize aminoacyl-tRNAs with G1–C72 base pairs

Chemical constituents of the leaves of rabbiteye blueberry (Vaccinium ashei) and characterisation of polymeric proanthocyanidins containing phenylpropanoid units and A-type linkages

Chemical constituents of the leaves of rabbiteye blueberry (Vaccinium ashei READE) were investigated in detail. The major phenolic components were caffeoyl quinic acids, flavonol glycosides, flavan-3-ols and proanthocyanidins. Catechins and proanthocyanidins having additional phenylpropanoid units, such as cinchonains, kandelins and mururins, characterised the polyphenols of this plant. Among them, vaccinin A, an isomer of mururin A, was found to be a new compound, and the structure was characterised by spectroscopic methods. The most abundant polyphenols (11.3% of freeze-dried leaves) were oligomeric proanthocyanidins. Thiol degradation with mercaptoethanol indicated that the polymer was constituted of (+)-catechin and (-)-epicatechin as the terminal units and (-)-epicatechin, procyanidin A-2, and cinchonains Ia and Ib as the extension units. Mass spectral analysis suggested the presence of at least dodecamers with A-type linkages and phenylpropanoid moieties