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Dietary Influence on Muscle Protein Synthesis and Hypertrophy
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
James McKendry, Stuart M. Phillips
The quest to unravel the complex control of important biological processes has been at the forefront of scientific research for many years. Following the discovery of rapamycin, in 1964 (93), a series of seminal studies utilized a genetic screen to identify genetic mutants (55) and determined that peptidyl-prolyl-isomerase FKBP12 was the cellular receptor for rapamycin (92). Furthermore, two targets of rapamycin (TOR) genes (TOR1 and TOR2) that encoded for two large kinases that resembled phosphoinositide 3-kinase (PI3-K) were identified (67), successfully pinpointing the biochemical mechanism of action. These significant breakthroughs paved the way for a plethora of research studies focused on TOR, and it is now understood that mTOR is an evolutionarily conserved serine/threonine kinase present in two structurally distinct protein complexes (i.e., mTORC1 and mTORC2). Both complexes play pivotal roles as integration hubs of numerous physiological stimuli. However, attention will be directed towards mTORC1-dependent mechanisms, as the role of this protein complex is the better characterized of the two protein complexes (68).
Cellular and Molecular Interactions in the Induction of Inflammation in Rheumatic Diseases
Published in Thomas F. Kresina, Monoclonal Antibodies, Cytokines, and Arthritis, 2020
The role of T cells in arthritis is clear, even though certain anticipated cytokines are absent within the synovium of patients. Although most forms of immunosuppressive therapy that benefit arthritis inhibit several aspects of immune function (1), specific inhibition of T cell function, in particular inhibition of lymphokine synthesis, ameliorates the disease process. In this regard, cyclosporin A (CsA), which acts specifically during T lymphocyte activation to inhibit the transcription of a limited set of early activation genes, including IL-2, IL-3, IFN-γ, TNF, and c-myc (92,93), effectively modulates the pathogenic events in certain subsets of rheumatoid arthritis patients (7). CsA binds to and inhibits cyclophilin, a peptidyl-prolyl isomerase responsbile for catalyzing the refolding of proteins and peptides into their native conformations during T cell activation (94,95). Comparison of high-dose (10 mg/kg) and low-dose (1 mg/kg) oral regimens in a prospective 6 month randomized, double-blind trial revealed that CsA significantly reduced disease activity by several parameters and improved function in a dose-related manner. Although drug-related toxicities occurred, these toxicities were often reversible with a reduction in the dose (7). These studies confirm the pivotal role of lymphocytes in the pathogenic process and point to additional related avenues of selective therapy.
Mitochondrial Dysfunction and Heart Diseases
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Another evidence of mitochondrial ROS in cardiac aging was shown by mice with a targeted mutation of the p66Shc gene. These mice display prolonged lifespan, reduced production of ROS, and increased resistance to ROS-mediated apoptosis.22. The p66Shc localizes to the mitochondrial intermembranous space and has been shown to be a mitochondrial redox enzyme, forming ROS by using electrons from the respiratory chain to produce H2O2.23 The p66Shc was phosphorylated by PKC-beta together with prolyl isomerase Pin-1, then the phosphorylated p66Shc accumulated within mitochondria to activate mitochondrial Ca2+ response, and subsequently induce apoptosis.24 Disruption of p66Shc prevents Angiotensin-II induced LV hypertrophy and cardiomyocytes apoptosis as well as reducing oxidative damage in endothelial cells in a diabetic mouse model.25
Pathogenic cis p-tau levels in CSF reflects severity of traumatic brain injury
Published in Neurological Research, 2022
Alireza Mohsenian Sisakht, Najme Karamzade-Ziarati, Amin Jahanbakhshi, Koorosh Shahpasand, Samareh Aghababaei, Omid Ahmadvand, Maziar Azar, Arash Fattahi, Selva Zamanzadeh
The other responsible factor is tau protein pathogenicity; starting with TBI and lasting till chronic sequelae [17]. Tau abnormalities are being observed in various neurodegenerative diseases, such as CTE and AD [18–20]. Tau protein is a microtubule-associated protein; which is expressed mainly in the axonal structure [21]. Tau is being moderately phosphorylated under physiological conditions; however, tau abnormal hyperphosphorylation reflects its aggregation and pathogenicity [17]. There are over 85 phosphorylation sites on tau protein and thus, it has been a matter of debate, which phosphorylation event triggers tau pathogenicity. It has been demonstrated that phosphorylated tau at Th231 exists in the two distinct cis and trans conformations; whose conversion is being mediated by peptidyl-prolyl isomerase Pin1. cis pT231-tau is extremely neurotoxic and an early driver of the tauopathy process upon TBI. We have shown that cis p-tau appears within hours of closed head injury and long before other known pathogenic p-tau species; including oligomers, pre-fibrillary and Neurofibrillary tangles [17].
Advances in preclinical approaches to Chagas disease drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Fernando Villalta, Girish Rachakonda
Cyclophilins (CyPs) are proteins with enzymatic peptidyl-prolyl isomerase activity (PPIase), essential for protein folding in vivo. Cyclosporin A (CsA) has a high binding affinity for CyPs and inhibits their PPIase activity. CsA has proven to have parasiticidal effects against some protozoa, including T. cruzi. Because CsA cannot be used in vivo since it has immunosuppressive properties [107], non-immunosuppressive CsA analogs originally synthesized by Novartis were used against T. cruzi. H-7–94 and F-7–62 were able to kill the three forms of the parasite, and had non-toxic effects for mammalian cells [108,109]. T. cruzi infected mice treated with H‐7‐94 and F‐7‐62 CsA analogs before and during the first 5 days post‐infection survived (100%) after parasite challenge and had significant lower parasitemia than non‐treated mice control (60% survival) [108].
Efficacy and safety of alisporivir for the treatment of hepatitis C infection
Published in Expert Opinion on Pharmacotherapy, 2019
Carol Stanciu, Anca Trifan, Cristina Muzica, Catalin Sfarti
Intracellular cyclophilin A is the essential element for HCV replication via its peptidyl-prolyl isomerase [28,29]. ALV is an oral, non-immunosuppressive, host-targeting antiviral agent that inhibits HCV replication by binding to host cyclophilin A and blocking its peptidyl-prolyl cis/trans isomerase activity [30–32]. Cyclophilin A binds to the non-structural 5A (NS5A) protein of all HCV genotypes, a process which is essential for HCV replication [33]. Thus, ALV, by inhibiting this action, has pangenotypic activity both in vitro and in clinical studies, and has a high barrier to the development of viral resistance [34,35]. Moreover, ALV in combination with DAAs has both an additive or synergetic effect with them and prevents the selection of HCV variants resistant to those agents [36].