scholarly journals mTOR: A Cellular Regulator Interface in Health and Disease

Cells ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 18 ◽  
Author(s):  
Fahd Boutouja ◽  
Christian M. Stiehm ◽  
Harald W. Platta
Keyword(s):  
Protein Composition ◽  
Mtor Inhibitors ◽  
Cellular Level ◽  
Serine Threonine Kinase ◽  
Central Function ◽  
Extend Life Span ◽  
Dependent Inhibition ◽  
Physiologic Function ◽  
Health And Disease

The mechanistic target of Rapamycin (mTOR) is a ubiquitously-conserved serine/threonine kinase, which has a central function in integrating growth signals and orchestrating their physiologic effects on cellular level. mTOR is the core component of differently composed signaling complexes that differ in protein composition and molecular targets. Newly identified classes of mTOR inhibitors are being developed to block autoimmune diseases and transplant rejections but also to treat obesity, diabetes, and different types of cancer. Therefore, the selective and context-dependent inhibition of mTOR activity itself might come into the focus as molecular target to prevent severe diseases and possibly to extend life span. This review provides a general introduction to the molecular composition and physiologic function of mTOR complexes as part of the Special Issue “2018 Select Papers by Cells’ Editorial Board Members”.

Regulation of renin processing and secretion: chemiosmotic control and novel secretory pathway

1993 ◽  
Vol 265 (2) ◽  
pp. C305-C320 ◽  
Author(s):  
J. A. King ◽  
D. J. Lush ◽  
J. C. Fray
Keyword(s):  
Secretory Pathway ◽  
Secretory Granules ◽  
Surface Membrane ◽  
Water Flux ◽  
Cellular Level ◽  
Macula Densa ◽  
Secretory Proteins ◽  
Juxtaglomerular Cells ◽  
Cl Channels ◽  
Health And Disease

The renin-angiotensin-aldosterone system (RAAS) plays an important role in cardiovascular and electrolyte regulation in health and disease. Juxtaglomerular cells in the kidney regulate endocrine RAAS by physiologically controlling conversion of prorenin and secretion of renin. The classical baroceptor, neurogenic, and macula densa mechanisms regulate renin expression at the cellular level by Ca2+, adenosine 3',5'-cyclic monophosphate (cAMP), and chemiosmotic forces (K+, Cl-, and water flux coupled to H+ movement). The baroceptor mechanism (through Ca2+) activates K+ and Cl- channels in the surface membrane and deactivates a KCl-H+ exchange chemiosmotic transporter in the secretory granular membrane. The neurogenic mechanism (through cAMP) promotes prorenin processing to renin. The macula densa mechanism (through K+ and Cl-) involves the processing of prorenin to renin. Ca2+, by inhibiting the KCl-H+ exchange transporter, prevents secretory granules from engaging in chemiosmotically mediated exocytosis. cAMP, on the other hand, by stimulating H+ influx, provides the acidic granular environment for prorenin processing to renin. It is concluded that, in the presence of a favorable chemiosmotic environment, prorenin is processed to renin, which may then be secreted by regulative degranulation or divergence translocation, a novel secretory pathway used by several secretory proteins, including renin.

Influence of carbohydrates on cell properties of Lactobacillus rhamnosus

2010 ◽  
Vol 5 (1) ◽  
pp. 103-110 ◽  
Author(s):  
Jelena Begovic ◽  
Djordje Fira ◽  
Amarela Terzic-Vidojevic ◽  
Ljubisa Topisirovic
Keyword(s):  
Growth Medium ◽  
Lactobacillus Rhamnosus ◽  
Cell Surface Hydrophobicity ◽  
Protein Composition ◽  
Surface Hydrophobicity ◽  
Cellular Level ◽  
Medium Composition ◽  
Producer Strain ◽  
Carbohydrate Source ◽  
Complex Relationships

AbstractLactobacilli represent normal commensals of the human body, particularly in the gut and vagina where they protect these environments from incoming pathogens via a variety of mechanisms. The influence of the carbohydrate source present in reconstituted MRS growth medium on the different cell properties of two Lactobacillus rhamnosus strains were examined. Two human vaginal isolates, BGHV719 and exopolysaccharide producer strain BGHV954 were analyzed. The results demonstrated that unlike in reconstituted MRS with glucose as a carbon source, the presence of fructose, mannose, or rhamnose, significantly reduced cell surface hydrophobicity of both strains. In addition, differences in cell wall protein composition of L. rhamnosus BGHV719 and alterations in colony mucoidity of L. rhamnosus BGHV954 were also demonstrated. Light and SEM microscopy revealed differences on the cellular level when BGHV719 was cultivated in the presence of different sugars. The results of this study point out the importance of complex relationships between growth medium composition and the different aspects of bacterial behavior, and call for more detailed analyses of versatile bacterial responses to the changes in the environment, including vaginal ecosystem. This is especially important since lactobacilli are amongst the most widely used of probiotics.

scholarly journals An Overview of Iron Metabolism in Health and Disease

2021 ◽  
pp. 70-78
Author(s):  
Nabiyev Abdusamat Utkurovich
Keyword(s):  
Cell Death ◽  
Iron Metabolism ◽  
Growth And Development ◽  
Biochemical Parameters ◽  
Cellular Level ◽  
The Body ◽  
Viral Diseases ◽  
Correct Interpretation ◽  
Working Capacity ◽  
Health And Disease

Human iron metabolism is the set of chemical reactions that maintain human homeostasis of iron at the systemic and cellular level. Iron is both necessary to the body and potentially toxic. Controlling iron levels in the body is a critically important part of many aspects of human health and disease. Iron deficiency states are the reason for a decrease in working capacity, an increase in susceptibility to viral diseases, especially in children and cause growth and development retardation. Iron overload and poisoning lead to the activation of processes that can cause cell death. Timely diagnosis of disorders of iron metabolism and subsequent monitoring of treatment require knowledge of not only pathophysiological mechanisms, but also methodological capabilities and correct interpretation of clinical and biochemical parameters of iron metabolism.

scholarly journals mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases

2018 ◽  
Author(s):  
Hannah E. Walters ◽  
Lynne S. Cox
Keyword(s):  
Cardiovascular Disease ◽  
Broad Spectrum ◽  
Molecular Mechanisms ◽  
Mtor Inhibitors ◽  
Chronological Age ◽  
Older Individuals ◽  
Serine Threonine Kinase ◽  
Age Related ◽  
Life Threatening ◽  
Current Therapies

Chronological age represents the greatest risk factor for many life-threatening diseases including neurodegeneration, cancer and cardiovascular disease; ageing also increases susceptibility to infectious disease. Current therapies that effectively tackle individual diseases may have little impact on the overall healthspan of older individuals, who would still be vulnerable to other age-related pathologies. However, recent progress in ageing research has highlighted the accumulation of senescent cells with chronological age as a probable underlying cause of pathological ageing. Cellular senescence is an essentially irreversible proliferation arrest mechanism that has important roles in development, wound healing and preventing cancer, but it may limit tissue function and cause widespread inflammation with age. The serine/threonine kinase mTOR is a regulatory nexus heavily implicated in both ageing and senescence. Excitingly, a growing body of research has highlighted rapamycin and other mTOR inhibitors as promising treatments for a broad spectrum of age-related pathologies, including neurodegeneration, cancer, immunosenescence, osteoporosis, rheumatoid arthritis, age-related blindness, diabetic nephropathy, muscular dystrophy, and cardiovascular disease. In this review, we assess the use of mTOR inhibitors to treat age-related pathologies, discuss possible molecular mechanisms of action where evidence is available, and consider strategies to minimize undesirable side effects. We also emphasize the urgent need for reliable, non-invasive biomarkers of senescence and biological ageing to better monitor the efficacy of any healthy ageing therapy.

P1752THE ROLE OF MTOR INHIBITORS ON CARDIOVASCULAR AGING IN RENAL TRANSPLANT PATIENTS WITH CHRONIC GRAFT DYSFUNCTION

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Barbara Infante ◽  
Giuseppe Castellano ◽  
Concetta Prisciandaro ◽  
Adelaide Dilorenzo ◽  
Francesco Bellanti ◽  
...  
Keyword(s):  
Renal Function ◽  
Gradient Centrifugation ◽  
Mtor Inhibitors ◽  
Left Ventricular ◽  
Mtor Inhibition ◽  
Central Function ◽  
Vitamina D ◽  
Protein Levels ◽  
Cardiovascular Aging ◽  
Fgf 23

Abstract Background and Aims Chronic Kidney Disease (CKD) is strongly associated with increased circulatory complications that can lead to accelerated cardiovascular aging. During CKD, persistent oxidative stress triggered by mitochondrial dysfunction can affect Klotho protein levels together with circulating FGF23. mTOR pathway is involved in pro-survival mechanism and can be differently modulated by several available therapeutics, therefore exerting central function in senescence, autophagy and cellular regeneration. The aim of this study was to evaluate the beneficial effect of mTOR inhibition on cardiovascular aging in transplanted patient with Chronic Allograft Dysfunction. Method In this study, 250 transplanted patients with calcineurin inhibitory (CNI) therapy and graft survival higher than 6 months and lower than 60 months were enrolled. The patients were then divided in three groups: (MMF group) patients undergoing CNI therapy with CS (Ciclosporin) and MMF, (mTOR Inhibitors group) patients undergoing CNI, CS and mTOR Inhibitors therapy and (MMF to mTOR Inhibitors group) with patients shifting from MMF to mTOR Inhibitors therapy. Renal function, FGF-23, Klotho, PTH, 1-25OH-Vitamina D, arterial stiffness by Pulse Wave Velocity (PWV), left ventricular hypertrophy expressed by the MSV and endothelial function by Flow Mediated Dilation (FMD) were measured. PBMC were isolated by gradient centrifugation. Results Between the MMF group and the mTOR Inhibitors groups we did not find significant differences in renal function, PTH, 1-25OH-Vitamina D, PRA, DSA, PWV, FM e DFE. However, FGF23, Klotho, phosphate levels were significantly changed. (FGF-23 pg/ml; p=0,00001; Klotho p=0,01; fosfaturia p=0,03; MMF group vs mTOR Inhibitors group) Interestingly, mTOR Inhibitors group patients showed a higher O2 consumption level associated to increased mitochondrial respiratory function. Pentraxin 3 (PTX-3) and p21 as inflammaging and senescence biomarkers were also detected to be significantly increased in MMF group compared to mTOR Inhibitors group (p=0,002). Conclusion In conclusion these data suggest that the use of mTOR Inhibitors in transplanted patients could prevent the occurrence of circulating complication and reduce the cardiovascular aging risk.

scholarly journals Rats genetically selected for low and high aerobic capacity exhibit altered soleus muscle myofilament functions

2020 ◽  
Vol 318 (2) ◽  
pp. C422-C429
Author(s):  
B. J. Biesiadecki ◽  
M. A. Brotto ◽  
L. S. Brotto ◽  
L. G. Koch ◽  
S. L. Britton ◽  
...  
Keyword(s):  
Muscle Force ◽  
Protein Composition ◽  
Contractile Properties ◽  
Muscle Type ◽  
Slow Fiber ◽  
Fast Fiber ◽  
Aerobic Exercise Capacity ◽  
Slow Type ◽  
Intact Muscle ◽  
Health And Disease

Aerobic exercise capacity is critical to bodily health. As a model to investigate the mechanisms that determine health and disease, we employed low (LCR) and high (HCR) capacity running rat models selectively bred to concentrate the genes responsible for divergent aerobic running capacity. To investigate the skeletal muscle contribution to this innate difference in running capacity we employed an approach combining examination of the myofilament protein composition and contractile properties of the fast fiber extensor digitorum longus (EDL) and slow fiber soleus (SOL) muscles from LCR and HCR rats. Intact muscle force experiments demonstrate that SOL, but not EDL, muscles from LCR rats exhibit a three times greater decrease in fatigued force. To investigate the mechanism of this increased fatigability in the LCR SOL muscle, we determined the myofilament protein composition and functional properties. Force-Ca2+ measurements demonstrate decreased Ca2+ sensitivity of single skinned SOL muscle fibers from LCR compared with that of HCR rats. Segregating SOL fibers into fast and slow types demonstrates that the decreased Ca2+ sensitivity in LCR SOL results from a specific decrease in slow-type SOL fiber Ca2+ sensitivity such that it was similar to that of fast-type fibers. These results identify that the altered myofilament contractile properties of LCR SOL slow-type fibers result in a fast muscle type Ca2+ sensitivity and the LCR muscle phenotype. Overall our findings demonstrate alterations of the myofilament proteins could contribute to fatigability of the SOL muscle and the decreased innate aerobic running performance of LCR compared with HCR rats.

Regulation of phosphatidylcholine and phosphatidylethanolamine synthesis in rat hepatocytes by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR)

2002 ◽  
Vol 362 (1) ◽  
pp. 97-104 ◽  
Author(s):  
Martin HOUWELING ◽  
Wil KLEIN ◽  
Math J. H. GEELEN
Keyword(s):  
Cellular Uptake ◽  
Rat Hepatocytes ◽  
Cellular Level ◽  
Membrane Phospholipids ◽  
Main Target ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Dose Dependent

The present study was undertaken to study the role of AMP-activated kinase (AMPK) in the biosynthesis of two major membrane phospholipids, phosphatidylcholine (PC) and phosphatidylethanolamine (PE). Incubation of rat hepatocytes with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), an activator of AMPK, produced dose-dependent inhibition of the incorporation of [3H]choline and [3H]ethanolamine into PC and PE, respectively. Determination of the cellular uptake of choline and ethanolamine showed that the reduced synthesis of PC and PE did not result from impaired uptake of these two precursors. The decreased synthesis of PC was not mirrored by a reduction in the activities of the enzymes of the CDP-choline pathway. The diminution of PE biosynthesis, however, was paralleled by a depressed activity of CTP:phosphoethanolamine cytidylyltransferase (ET), the pace-setting enzyme of the CDP-ethanolamine pathway. AICAR treatment of hepatocytes stimulated the conversion of choline into betaine, indicating that reduced PC synthesis most probably resulted from a decrease in the availability of choline. In addition, AICAR induced a 50% reduction in the cellular level of diacylglycerols, which may further impair the synthesis of PC and PE. The results thus indicate that AICAR inhibits the biosynthesis of PC and PE and that the effect is exerted at different sites in the two pathways. Increased oxidation of choline to betaine is the main target of AICAR in the PC pathway, whereas inhibition of ET activity is the locus of AICAR action in the PE pathway.

scholarly journals A novel Microproteomic Approach Using Laser Capture Microdissection to Study Cellular Protrusions

2019 ◽  
Vol 20 (5) ◽  
pp. 1172 ◽  
Author(s):  
Karine Gousset ◽  
Ana Gordon ◽  
Shravan Kumar Kannan ◽  
Joey Tovar
Keyword(s):  
Laser Capture Microdissection ◽  
Protein Extraction ◽  
Cell Communication ◽  
Protein Composition ◽  
Fluorescent Markers ◽  
Different Types ◽  
Health And Disease ◽  
Multicellular Organisms ◽  
First Time ◽  
Laser Capture

Cell–cell communication is vital to multicellular organisms, and distinct types of cellular protrusions play critical roles during development, cell signaling, and the spreading of pathogens and cancer. The differences in the structure and protein composition of these different types of protrusions and their specific functions have not been elucidated due to the lack of a method for their specific isolation and analysis. In this paper, we described, for the first time, a method to specifically isolate distinct protrusion subtypes, based on their morphological structures or fluorescent markers, using laser capture microdissection (LCM). Combined with a unique fixation and protein extraction protocol, we pushed the limits of microproteomics and demonstrate that proteins from LCM-isolated protrusions can successfully and reproducibly be identified by mass spectrometry using ultra-high field Orbitrap technologies. Our method confirmed that different types of protrusions have distinct proteomes and it promises to advance the characterization and the understanding of these unique structures to shed light on their possible role in health and disease.

Conserved sequence motifs and the structure of the mTOR kinase domain

2013 ◽  
Vol 41 (4) ◽  
pp. 889-895 ◽  
Author(s):  
Evelyn Sauer ◽  
Stefan Imseng ◽  
Timm Maier ◽  
Michael N. Hall
Keyword(s):  
Crystal Structure ◽  
Catalytic Domain ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Homology Model ◽  
Kinase Domain ◽  
Sequence Motifs ◽  
Serine Threonine Kinase ◽  
Conserved Sequence ◽  
Mtor Kinase

The atypical serine/threonine kinase mTOR (mammalian target of rapamycin) is a central regulator of cell growth and metabolism. mTOR is part of two multisubunit signalling complexes, mTORC1 and mTORC2. Although many aspects of mTOR signalling are understood, the lack of high-resolution structures impairs a detailed understanding of complex assembly, function and regulation. The structure of the kinase domain is of special interest for the development of mTOR inhibitors as anti-cancer agents. A homology model of the mTOR kinase domain was derived from the structure of PI3Ks (phosphoinositide 3-kinases). More recently, the crystal structure of the catalytic domain of human mTOR was determined, providing long-awaited structural insight into the architecture of mTOR. Interestingly, the homology model predicted several aspects of the crystal structure. In the present paper, we revisit the homology model in the context of the now available crystal structure of the mTOR kinase domain.

scholarly journals Neuroprotective effects of physical exercise: Implications in health and disease

2021 ◽  
Vol 68 (3) ◽  
pp. 383-389
Author(s):  
Sebastian Romeo Pintilie ◽  
◽  
Alice D. Condrat ◽  
Adriana Fodor ◽  
Adela-Viviana Sitar-Tăut ◽  
...  
Keyword(s):  
Physical Activity ◽  
Physical Exercise ◽  
Molecular Mechanisms ◽  
Cellular Level ◽  
Neuroprotective Effects ◽  
Chemical Effects ◽  
Physical Exercises ◽  
Health And Disease ◽  
Molecular Aspects ◽  
The Brain

Physical exercises have long been linked to numerous health improvements, ranging from cardiovascular to psychiatric. In this review, we take a closer look on its anatomical, physiological and chemical effects on the brain. Starting from the clinical to the cellular level, we will analyze the neurogenesis, anti-inflammatory effects on Brain-Blood Barrier and synaptic plasticity, outlining known molecular aspects that are influenced by physical activity, such as: gene expression, changes of growth factors and neurotransmitter levels and means of reverting molecular mechanisms of ageing. The brain derived neurotrophic factor (BDNF) is one of the central molecules that links the physical exercise to neurogenesis, neuroprotection, cognitive functions, dendritic growth, memory formation and many more. We indicate the correlation between physical activity and mental health in diseases like depression, Alzheimer’s dementia and Parkinson’s disease.

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