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Robert G. Keynes Anastasia Karchevskaya Dieter Riddall Charmaine H. Griffiths Tomas C. Bellamy A. W. Edith Chan David L. Selwood John Garthwaite 《Chemical biology & drug design》2019,94(3):1680-1693
During some investigations into the mechanism of nitric oxide consumption by brain preparations, several potent inhibitors of this process were identified. Subsequent tests revealed the compounds act by inhibiting lipid peroxidation, a trigger for a form of regulated cell death known as ferroptosis. A quantitative structure–activity study together with XED (eXtended Electron Distributions) field analysis allowed a qualitative understanding of the structure–activity relationships. A representative compound N‐(3,5‐dimethyl‐4H‐1,2,4‐triazol‐4‐yl)‐10H‐phenothiazine‐10‐carboxamide (DT‐PTZ‐C) was able to inhibit completely oxidative damage brought about by two different procedures in organotypic hippocampal slice cultures, displaying a 30‐ to 100‐fold higher potency than the standard vitamin E analogue, Trolox or edaravone. The compounds are novel, small, drug‐like molecules of potential therapeutic use in neurodegenerative disorders and other conditions associated with oxidative stress. 相似文献
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Fausto Biancari Tomas Gudbjartsson Jouni Heikkinen Vesa Anttila Timo Mäkikallio Anders Jeppsson Linda Thimour-Bergström Carmelo Mignosa Antonino S. Rubino Kari Kuttila Jarmo Gunn Jan-Ola Wistbacka Kari Teittinen Kari Korpilahti Francesco Onorati Giuseppe Faggian Giulia Vinco Corrado Vassanelli Flavio Ribichini Tatu Juvonen Tomas A. Axelsson Axel F. Sigurdsson Pasi P. Karjalainen Ari Mennander Olli Kajander Markku Eskola Erkki Ilveskoski Veronica D'Oria Marisa De Feo Tuomas Kiviniemi K.E. Juhani Airaksinen 《The American journal of cardiology》2014
156.
Esther Phielix Tomas Jelenik Peter Nowotny Julia Szendroedi Michael Roden 《Diabetologia》2014,57(3):572-581
Aims/hypothesis
Muscle mitochondrial function can vary during fasting, but is lower during hyperinsulinaemia in insulin-resistant humans. Ageing and hyperlipidaemia may be the culprits, but the mechanisms remain unclear. We hypothesised that (1) insulin would fail to increase mitochondrial oxidative capacity in non-diabetic insulin-resistant young obese humans and in elderly patients with type 2 diabetes and (2) reducing NEFA levels would improve insulin sensitivity by raising oxidative capacity and lowering oxidative stress.Methods
Before and after insulin (4, 40, 100 nmol/l) stimulation, mitochondrial oxidative capacity was measured in permeabilised fibres and isolated mitochondria using high-resolution respirometry, and H2O2 production was assessed fluorimetrically. Tissue-specific insulin sensitivity was measured with hyperinsulinaemic–euglycaemic clamps combined with stable isotopes. To test the second hypothesis, in a 1-day randomised, crossover study, 15 patients with type 2 diabetes recruited via local advertisement were assessed for eligibility. Nine patients fulfilled the inclusion criteria (BMI <35 kg/m2; age <65 years) and were allocated to and completed the intervention, including oral administration of 750 mg placebo or acipimox. Blinded randomisation was performed by the pharmacy; all participants, researchers performing the measurements and those assessing study outcomes were blinded. The main outcome measures were insulin sensitivity, oxidative capacity and oxidative stress.Results
Insulin sensitivity and mitochondrial oxidative capacity were ~31% and ~21% lower in the obese groups than in the lean group. The obese participants also exhibited blunted substrate oxidation upon insulin stimulation. In the patients with type 2 diabetes, acipimox improved insulin sensitivity by ~27% and reduced H2O2 production by ~45%, but did not improve basal or insulin-stimulated mitochondrial oxidative capacity. No harmful treatment side effects occurred.Conclusions/interpretation
Decreased mitochondrial oxidative capacity can also occur independently of age in insulin-resistant young obese humans. Insulin resistance is present at the muscle mitochondrial level, and is not affected by reducing circulating NEFAs in type 2 diabetes. Thus, impaired plasticity of mitochondrial function is an intrinsic phenomenon that probably occurs independently of lipotoxicity and reduced glucose uptake. Trial registration Clinical Trials NCT00943059 Funding This study was funded in part by a grant from the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD e.V.). 相似文献157.
Ming-Dong Zhang Giuseppe Tortoriello Brian Hsueh Raju Tomer Li Ye Nicholas Mitsios Lotta Borgius Gunnar Grant Ole Kiehn Masahiko Watanabe Mathias Uhlén Jan Mulder Karl Deisseroth Tibor Harkany Tomas G. M. H?kfelt 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(12):E1149-E1158
Neuronal calcium (Ca2+)-binding proteins 1 and 2 (NECAB1/2) are members of the phylogenetically conserved EF-hand Ca2+-binding protein superfamily. To date, NECABs have been explored only to a limited extent and, so far, not at all at the spinal level. Here, we describe the distribution, phenotype, and nerve injury-induced regulation of NECAB1/NECAB2 in mouse dorsal root ganglia (DRGs) and spinal cord. In DRGs, NECAB1/2 are expressed in around 70% of mainly small- and medium-sized neurons. Many colocalize with calcitonin gene-related peptide and isolectin B4, and thus represent nociceptors. NECAB1/2 neurons are much more abundant in DRGs than the Ca2+-binding proteins (parvalbumin, calbindin, calretinin, and secretagogin) studied to date. In the spinal cord, the NECAB1/2 distribution is mainly complementary. NECAB1 labels interneurons and a plexus of processes in superficial layers of the dorsal horn, commissural neurons in the intermediate area, and motor neurons in the ventral horn. Using CLARITY, a novel, bilaterally connected neuronal system with dendrites that embrace the dorsal columns like palisades is observed. NECAB2 is present in cell bodies and presynaptic boutons across the spinal cord. In the dorsal horn, most NECAB1/2 neurons are glutamatergic. Both NECAB1/2 are transported into dorsal roots and peripheral nerves. Peripheral nerve injury reduces NECAB2, but not NECAB1, expression in DRG neurons. Our study identifies NECAB1/2 as abundant Ca2+-binding proteins in pain-related DRG neurons and a variety of spinal systems, providing molecular markers for known and unknown neuron populations of mechanosensory and pain circuits in the spinal cord.Calcium (Ca2+) plays a crucial role in many and diverse cellular processes, including neurotransmission (1). Glutamate and neuropeptides are neurotransmitters released from the central terminals of dorsal root ganglion (DRG) neurons in the spinal dorsal horn, where signals for different sensory modalities, including pain, are conveyed to higher centers (2–12). Neurotransmitter release is tightly regulated by Ca2+-dependent SNARE proteins whose activity is regulated by Ca2+-binding proteins (CaBPs) (1, 7, 13).Parvalbumin (PV), calbindin D-28K (CB), calretinin (CR), and secretagogin (Scgn) are extensively studied EF-hand CaBPs, and they have also emerged as valuable anatomical markers for morphologically and functionally distinct neuronal subpopulations (14–17). The expression of CaBPs in DRG neurons has been thoroughly studied (18). Moreover, neuronal Ca2+ sensor 1 and downstream regulatory element-antagonist modulator (DREAM) are also EF-hand Ca2+-binding proteins in DRGs and the spinal cord (19, 20). Despite these advances, a CaBP has so far not been characterized in the majority of small- and medium-sized DRG neurons, many of which represent nociceptors.The subfamily of neuronal Ca2+-binding proteins (NECABs) consists of three members (NECAB1–NECAB3), probably as a result of gene duplication (21). NECABs are also EF-hand proteins, with one pair of EF-hand motifs in the N terminus and a putative antibiotic biosynthesis monooxygenase domain in the C terminus, which are linked by a NECAB homogeneous region (22). NECAB1/2 are restricted to the nervous system, whereas NECAB3 is also expressed in the heart and skeletal muscle (21).NECAB1 was first identified as the target protein of synaptotagmin I C2A-domain by affinity chromatography, with its expression restricted to layer 4 cortical pyramidal neurons, inhibitory interneurons, and hippocampal CA2 pyramidal cells in mouse brain (21, 23). The gene of the second member was cloned from mouse and initially named Necab. It encodes a 389-aa (NECAB2) (24). NECAB2 was identified as a downstream target of Pax6 in mouse retina, which is involved in retinal development (24, 25), as well as being a binding partner for the adenosine A2A receptor (22). Furthermore, an interaction between NECAB2 and metabotropic glutamate receptor 5 (mGluR5) was demonstrated in rat hippocampal pyramidal cells, possibly regulating mGluR5’s coupling to its signaling machinery (26). Finally, NECAB3, also known as XB51, was isolated as an interacting target for the neuron-specific X11-like protein and is possibly involved in the pathogenesis of Alzheimer’s disease (27, 28).Very recently, NECAB1/2 were shown to have complementary expression patterns in mouse hippocampus at the mRNA and protein levels, whereas NECAB3 is broadly distributed in the hippocampus (29). NECAB1-expressing cells were seen throughout the cell-sparse layers of Ammon’s horn and the hilus of the dentate gyrus. In contrast, NECAB2 is enriched in pyramidal cells of the CA2 region. A minority of NECAB1+ neurons were GABAergic yet did not coexpress PV, CB, or CR (29).Here, we investigated the expression of NECAB1/2 in mouse DRGs and spinal cord using quantitative PCR (qPCR), immunohistochemistry (also combined with CLARITY) (30), and Western blotting. We compared the distribution of NECABs with that of the four CaBPs restricted to neurons, PV, CB, CR, or Scgn. NECAB+ neurons in the spinal dorsal horn were phenotyped using transgenic mice harboring genetic markers for excitatory [vesicular glutamate transporter 2 (VGLUT2)] (31) or inhibitory [glutamate decarboxylase 67 (GAD67)] (32) cell identities. Finally, the effect of peripheral nerve injury was analyzed. 相似文献
158.
We hypothesized that decreasing elevated night‐time heart rate (HR) in hypertension by administering a bradycardic agent (ivabradine) at bedtime could bring cardiovascular benefit. Since rats are nocturnal animals, they exhibit circadian rhythms phase‐shifted relative to humans. Sixty‐six Wistar rats were divided into non‐diseased controls and rats with l ‐NAME‐induced hypertension to compare the haemodynamic effects of daytime‐dosed and night‐time‐dosed ivabradine. l ‐NAME‐induced hypertension inverted the physiological 5.6% night‐to‐day HR dip to an undesirable HR rise by 11.1%. Ivabradine dosed at daytime (the rat's resting phase) reverted a night‐to‐day HR rise to HR dip by 14.2%. These results suggest a cardiovascular benefit of ivabradine dosed at the human's resting phase (night‐time) for hypertensive patients with nondipping HR. 相似文献
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Roza Chaireti Rupesh Rajani Annika Bergquist Tor Melin Inga-Lill Friis-Liby Marjo Kapraali Stergios Kechagias Tomas L. Lindahl Sven Almer 《Thrombosis research》2014