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Martin Lund Kathrine G. Andersen Robert Heaton Iain P. Hargreaves Niels Gregersen Rikke K.J. Olsen 《生物化学与生物物理学报:疾病的分子基础》2021,1867(6):166100
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is the most common inborn long-chain fatty acid oxidation (FAO) disorder. VLCAD deficiency is characterized by distinct phenotypes. The severe phenotypes are potentially life-threatening and affect the heart or liver, with a comparatively milder phenotype characterized by myopathic symptoms. There is an unmet clinical need for effective treatment options for the myopathic phenotype. The molecular mechanisms driving the gradual decrease in mitochondrial function and associated alterations of muscle fibers are unclear.The peroxisome proliferator-activated receptor (PPAR) pan-agonist bezafibrate is a potent modulator of FAO and multiple other mitochondrial functions and has been proposed as a potential medication for myopathic cases of long-chain FAO disorders. In vitro experiments have demonstrated the ability of bezafibrate to increase VLCAD expression and activity. However, the outcome of small-scale clinical trials has been controversial.We found VLCAD deficient patient fibroblasts to have an increased oxidative stress burden and deranged mitochondrial bioenergetic capacity, compared to controls. Applying heat stress under fasting conditions to bezafibrate pretreated patient cells, caused a marked further increase of mitochondrial superoxide levels. Patient cells failed to maintain levels of the essential thiol peptide antioxidant glutathione and experienced a decrease in cellular viability. Our findings indicate that chronic PPAR activation is a plausible initiator of long-term pathogenesis in VLCAD deficiency. Our findings further implicate disruption of redox homeostasis as a key pathogenic mechanism in VLCAD deficiency and support the notion that a deranged thiol metabolism might be an important pathogenic factor in VLCAD deficiency. 相似文献
995.
Cristiane Miranda da Silva Mayara Peres Leal Robson Alexandre Brochetti Tárcio Braga Luana Beatriz Vitoretti Niels Olsen Saraiva Camara Amílcar Sabino Damazo Ana Paula Ligeiro-de-Oliveira Maria Cristina Chavantes Adriana Lino-dos-Santos-Franco 《PloS one》2015,10(11)
Lung diseases constitute an important public health problem and its growing level of concern has led to efforts for the development of new therapies, particularly for the control of lung inflammation. Low Level Laser Therapy (LLLT) has been highlighted as a non-invasive therapy with few side effects, but its mechanisms need to be better understood and explored. Considering that pollution causes several harmful effects on human health, including lung inflammation, in this study, we have used formaldehyde (FA), an environmental and occupational pollutant, for the induction of neutrophilic lung inflammation. Our objective was to investigate the local and systemic effects of LLLT after FA exposure. Male Wistar rats were exposed to FA (1%) or vehicle (distillated water) during 3 consecutive days and treated or not with LLLT (1 and 5 hours after each FA exposure). Non-manipulated rats were used as control. 24 h after the last FA exposure, we analyzed the local and systemic effects of LLLT. The treatment with LLLT reduced the development of neutrophilic lung inflammation induced by FA, as observed by the reduced number of leukocytes, mast cells degranulated, and a decreased myeloperoxidase activity in the lung. Moreover, LLLT also reduced the microvascular lung permeability in the parenchyma and the intrapulmonary bronchi. Alterations on the profile of inflammatory cytokines were evidenced by the reduced levels of IL-6 and TNF-α and the elevated levels of IL-10 in the lung. Together, our results showed that LLLT abolishes FA-induced neutrophilic lung inflammation by a reduction of the inflammatory cytokines and mast cell degranulation. This study may provide important information about the mechanisms of LLLT in lung inflammation induced by a pollutant. 相似文献
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Nathalie Strutz-Seebohm Ilona Gutcher Niels Decher Klaus Steinmeyer Florian Lang Guiscard Seebohm 《Cellular physiology and biochemistry》2007,20(6):791-800
In this study, we analysed the inhibitory potency, blocking characteristics and putative binding sites of three structurally distinct Kv1.5 channel inhibitors on cloned human Kv1.5 channels. Obtained IC(50) values for S9947, MSD-D and ICAGEN-4 were 0.7 microM, 0.5 microM, and 1.6 microM, respectively. The Hill-coefficients were close to 1 for S9947 and approximately 2 for MSD-D and ICAGEN-4. All three compounds inhibited Kv1.5 channels preferentially in the open state, with Kv1.5 block displaying positive frequency dependence, but no clear voltage and potassium dependence. In contrast to slow on- and off-rates of apparent binding of MSD-D and ICAGEN-4, S9947 had fast on- and off-rates resulting in faster adaptation to changes in pulse frequency. Utilizing Alanine-scanning and in silico modeling we suggest binding of the compounds to the central cavity with crucial residues Ile508 and Val512 in the S6-segment. Residue Thr480 located at the base of the selectivity filter is important for ICAGEN-4 and S9947 inhibition, but less so for MSD-D binding. Our docking models suggest that the innermost potassium ion in the selectivity filter may form a tertiary complex with oxygens of S9947 and ICAGEN-4 and residue Thr480. This binding component is absent in the MSD-D block. As S9947 and ICAGEN-4 show faster block with proceeding channel openings, formation of this tertiary complex may increasingly stabilise binding of S9947 and ICAGEN-4, thereby explaining open channel block kinetics of these compounds. 相似文献
998.
Dr. Frank Schneider Thomas Elbert Hans Heimann Andreas Welker Friedhelm Stetter Regina Mattes Niels Birbaumer Karl Mann 《Applied psychophysiology and biofeedback》1993,18(1):23-32
Ten unmedicated alcohol-dependent male inpatients participated in a Slow Cortical Potential (SCP) self-regulation task utilizing biofeedback and instrumental conditioning. These patients were hospitalized for treatment of alcohol dependency after chronic abuse of alcoholic beverages. Somatic withdrawal symptomatology had occurred recently and the patients were free of any withdrawal symptoms of the autonomic nervous system. Immediately after hospitalization patients were unable to control their SCPs without the reinforcement of immediate feedback across 4 sessions. Seven patients participated in a fifth session an average of 4 months later. Six out of these 7 patients had not had a relapse at the follow-up. In the fifth session these patients were immediately able to differentiate between the required negativity and negativity suppression, whereas the seventh patient, who had relapsed, was unable to control his brain potentials successfully. Results are further evidence that some of the frontocortical dysfunctions in alcohol-dependent patients are reversible. This could covary with a morphological restitution of the cortex. 相似文献
999.
High-level expression of the hisHAFI genes in Escherichia coli, cloned under the control of an IPTG-inducible promoter, caused filamentation, as previously reported in Salmonella typhimurium. We speculated that this filamentation might be produced by an action of the HisH and HisF enzymes on their product AICAR (amino-imidazole carboxamide riboside 5′-phosphate), a histidine by-product and normal purine precursor, possibly by favouring the formation of ZTP, the triphosphate derivative of AICAR. However, filamentation occured even in the absence of carbon flow through the histidine and purine pathways, as observed in a hisG purF strain lacking the first enzyme in each pathway. Filamentation thus does not require either the normal substrate or products of the overproduced histidine enzymes and must reflect another activity. 相似文献