1,721,261 research outputs found
A viewpoint about Lenadogene nolparvovec failing to meet its primary endpoint even though it permanently corrects the m.11778G>A mutation causative of LHON
No full textThe aerobic mitochondrial ATP synthesis from a comprehensive point of view
No full textMost of the ATP to satisfy the energetic demands of the cell is produced by the F1Fo-ATP synthase (ATP synthase) which can also function outside the mitochondria. Active oxidative phosphorylation (OxPhos) was shown to operate in the photoreceptor outer segment, myelin sheath, exosomes, microvesicles, cell plasma membranes and platelets. The mitochondria would possess the exclusive ability to assemble the OxPhos molecular machinery so to share it with the endoplasmic reticulum (ER) and eventually export the ability to aerobically synthesize ATP in true extra-mitochondrial districts. The ER lipid rafts expressing OxPhos components is indicative of the close contact of the two organelles, bearing different evolutionary origins, to maximize the OxPhos efficiency, exiting in molecular transfer from the mitochondria to the ER. This implies that its malfunctioning could trigger a generalized oxidative stress. This is consistent with the most recent interpretations of the evolutionary symbiotic process whose necessary prerequisite appears to be the presence of the internal membrane system inside the eukaryote precursor, of probable archaeal origin allowing the engulfing of the α-proteobacterial precursor of mitochondria. The process of OxPhos in myelin is here studied in depth. A model is provided contemplating the biface arrangement of the nanomotor ATP synthase in the myelin sheath.Most of the ATP to satisfy the energetic demands of the cell is produced by the F1Fo-ATP synthase (ATP synthase) which can also function outside the mitochondria. Active oxidative phosphorylation (OxPhos) was shown to operate in the photoreceptor outer segment, myelin sheath, exosomes, microvesicles, cell plasma membranes and platelets. The mitochondria would possess the exclusive ability to assemble the OxPhos molecular machinery so to share it with the endoplasmic reticulum (ER) and eventually export the ability to aerobically synthesize ATP in true extra-mitochondrial districts. The ER lipid rafts expressing OxPhos components is indicative of the close contact of the two organelles, bearing different evolutionary origins, to maximize the OxPhos efficiency, exiting in molecular transfer from the mitochondria to the ER. This implies that its malfunctioning could trigger a generalized oxidative stress. This is consistent with the most recent interpretations of the evolutionary symbiotic process whose necessary prerequisite appears to be the presence of the internal membrane system inside the eukaryote precursor, of probable archaeal origin allowing the engulfing of the alpha -proteobacterial precursor of mitochondria. The process of OxPhos in myelin is here studied in depth. A model is provided contemplating the biface arrangement of the nanomotor ATP synthase in the myelin sheath
Preclinical Evidence of Withania somnifera and Cordyceps spp.: Neuroprotective Properties for the Management of Alzheimer's Disease
No full text: Alzheimer's disease (AD) is considered one of the main pathologies of our time, whose incidence and prevalence are suggested to be strongly underestimated. AD presents as a complex neurodegenerative condition characterized by marked neuroinflammation and a significant decline in the cognitive and mnemonic functions of affected patients. Recognized AD pathological hallmarks include amyloid beta plaque and neurofibrillary tangle formation, synaptic dysfunction with considerable apoptosis of cholinergic and dopaminergic neurons, and high levels of oxidative stress and neuroinflammation. The available pharmacological treatments are represented by acetylcholinesterase inhibitors to treat the mild to moderate form of the disease and N-methyl-D-aspartate inhibitors alone or in combination with the previously cited ones in the late stage of the neurodegenerative condition. Furthermore, emerging drug therapies such as monoclonal antibodies are promising agents in AD management. Although scientific evidence highlights these chemicals as effective in slowing down disease progression, significant limitations behind their employment derive from the notable dose-dependent side effects and the single-target mechanism of action. In this context, two well-studied phytotherapeutics, W. somnifera (W. somnifera) and fungi belonging to the genus Cordyceps, have gained attention for their chemical composition regarding their neuroprotective and anti-inflammatory effects. Ashwagandha (obtained principally from the roots of W. somnifera) is an adaptogen that relieves stress and anxiety. It contains several ergostane-type steroidal lactones-such as withanolides and withaferin A-and various alkaloids, contributing to its antioxidant and neuroprotective effects. Likewise, cordycepin is the main bioactive principle found in Cordyceps fungi. This natural nucleoside has been reported to possess therapeutic potential as an anti-cancer, immunomodulatory, and anti-inflammatory agent, with some studies suggesting a beneficial role in AD treatment. The purpose of the present review is to investigate the pharmacological properties of W. somnifera and Cordyceps species in the context of AD treatment and explore the therapeutic potential of the constitutive bioactive molecules in preclinical models mimicking this neurodegenerative condition
Why is an energy metabolic defect the common outcome in BMFS?
No full textInherited bone marrow failure syndromes (BMFS) are rare, distressing, inherited blood disorders of children. Although the genetic origin of these pathologies involves genes with different functions, all are associated with progressive haematopoietic impairment and an excessive risk of malignancies. Defects in energy metabolism induce oxidative stress, impaired energy production and an unbalanced ratio between ATP and AMP. This assumes an important role in self-renewal and differentiation in haematopoietic stem cells (HSC) and can play an important role in bone marrow failure. Defects in energetic/respiratory metabolism, in particular in FA and SDS cells, have been described recently and seem to be a pertinent argument in the discussion of the haematopoietic defect in BMFS, as an alternative to the hypotheses already established on this subject, which may shed new light on the evolution of these diseases
Neurocognitive functioning impairment after anti-cancer drug treatment:which is the link with demyelination? (RE: Neurocognitive functioning in adult survivors of childhood non-central nervous system cancer
No full textRole of myelin sheath energy metabolism in neurodegenerative diseases
No full textMore than any other organs, brain energy demand is entirely dependent on glucose catabolism through the oxidative phosphorylation (OXPHOS). Glucose is the major cerebral energy substrate in the nervous system (NS). Ketone bodies can be utilized as an additional substrate, but in any case, neurons critically depend on oxygen supply. This sounds quite surprising considering that NS contains few mitochondria, which are universally considered the exclusive site of OXPHOS. Several authors have hypothesized that glia may be involved in the energetic support of the axon, supposing an unknown trophic role played by myelin sheath. In fact, the myelin-forming cells, i.e., oligodendrocytes and Schwann cells in central and peripheral NS, respectively, appear fundamental for the maintenance of long-term axonal functional integrity
The Liaison between Metabolism and Oxidative Stress in Human Diseases
No full textMitochondria have been the prerequisite to eukaryote complexity since their likely endosymbiotic origin, allowing a remarkable expansion in the number of genes expressed [...
Simultaneous Detection of Activity and Relative Molecular Mass of Adenylate Kinases After SDS-PAGE and Blotting
No full textAdenylate kinases (AKs) are ubiquitous monomeric phosphotransferases, which play a pivotal role in the energetic metabolism. At the present, nine isoforms are known. AKs catalyze the following reversible reaction: ATP + AMP â 2 ADP, even though isoform 3 uses GTP instead ATP. For many years, the activity of AKs has been detected only after native polyacrylamide gel separations, i.e. in the absence of sodium dodecyl sulfate or methanol. In this work, we report the possibility to detect the activity of the isoforms able to use ATP as substrate, directly onto gel or nitrocellulose sheets, after denaturing SDS-PAGE and electroblotting. This method is innovative because it allows to determine simultaneously the activity and the molecular weight of AKs, especially onto nitrocellulose where bands are sharper, thanks to absence of protein diffusion
Direct electric current from low voltage for the inactivation of venom enzymes: may this be a future direction?
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