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Human Cell Mar 2022The Proviral Integration of Molony murine leukemia virus (PIM)-1 protein contributes to the solid cancers and hematologic malignancies, cell growth, proliferation,... (Review)
Review
The Proviral Integration of Molony murine leukemia virus (PIM)-1 protein contributes to the solid cancers and hematologic malignancies, cell growth, proliferation, differentiation, migration, and other life activities. Many studies have related these functions to its molecular structure, subcellular localization and expression level. However, recognition of specific active sites and their effects on the activity of this constitutively active kinase is still a challenge. Based on the close relationship between its molecular structure and functional activity, this review covers the specific residues involved in the binding of ATP and different substrates in its catalytic domain. This review then elaborates on the relevant changes in protein conformation and cell functions after PIM-1 binds to different substrates. Therefore, this intensive study can improve the understanding of PIM-1-regulated signaling pathways by facilitating the discovery of its potential phosphorylation substrates.
Topics: Animals; Catalytic Domain; Cell Proliferation; Hematologic Neoplasms; Mice; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-pim-1
PubMed: 35000143
DOI: 10.1007/s13577-021-00656-3 -
Redox Report : Communications in Free... Dec 2018p53 is a tumor suppressor protein involved in regulating a wide array of signaling pathways. The role of p53 in the cell is determined by the type of imposed oxidative... (Review)
Review
BACKGROUND
p53 is a tumor suppressor protein involved in regulating a wide array of signaling pathways. The role of p53 in the cell is determined by the type of imposed oxidative stress, its intensity and duration. The last decade of research has unravelled a dual nature in the function of p53 in mediating the oxidative stress burden. However, this is dependent on the specific properties of the applied stress and thus requires further analysis.
METHODS
A systematic review was performed following an electronic search of Pubmed, Google Scholar, and ScienceDirect databases. Articles published in the English language between January 1, 1990 and March 1, 2017 were identified and isolated based on the analysis of p53 in skeletal muscle in both animal and cell culture models.
RESULTS
Literature was categorized according to the modality of imposed oxidative stress including exercise, diet modification, exogenous oxidizing agents, tissue manipulation, irradiation, and hypoxia. With low to moderate levels of oxidative stress, p53 is involved in activating pathways that increase time for cell repair, such as cell cycle arrest and autophagy, to enhance cell survival. However, with greater levels of stress intensity and duration, such as with irradiation, hypoxia, and oxidizing agents, the role of p53 switches to facilitate increased cellular stress levels by initiating DNA fragmentation to induce apoptosis, thereby preventing aberrant cell proliferation.
CONCLUSION
Current evidence confirms that p53 acts as a threshold regulator of cellular homeostasis. Therefore, within each modality, the intensity and duration are parameters of the oxidative stressor that must be analyzed to determine the role p53 plays in regulating signaling pathways to maintain cellular health and function in skeletal muscle.
ABBREVIATIONS
Acadl: acyl-CoA dehydrogenase, long chain; Acadm: acyl-CoA dehydrogenase, C-4 to C-12 straight chain; AIF: apoptosis-inducing factor; Akt: protein kinase B (PKB); AMPK: AMP-activated protein kinase; ATF-4: activating transcription factor 4; ATM: ATM serine/threonine kinase; Bax: BCL2 associated X, apoptosis regulator; Bcl-2: B cell Leukemia/Lymphoma 2 apoptosis regulator; Bhlhe40: basic helix-loop-helix family member e40; BH3: Borane; Bim: bcl-2 interacting mediator of cell death; Bok: Bcl-2 related ovarian killer; COX-IV: cytochrome c oxidase IV; cGMP: Cyclic guanosine monophosphate; c-myc: proto-oncogene protein; Cpt1b: carnitine palmitoyltransferase 1B; Dr5: death receptor 5; eNOS: endothelial nitric oxide synthase; ERK: extracellular regulated MAP kinase; Fas: Fas Cell surface death receptor; FDXR: Ferredoxin Reductase; FOXO3a: forkhead box O3; Gadd45a: growth arrest and DNA damage-inducible 45 alpha; GLS2: glutaminase 2; GLUT 1 and 4: glucose transporter 1(endothelial) and 4 (skeletal muscle); GSH: Glutathione; Hes1: hes family bHLH transcription factor 1; Hey1: hes related family bHLH transcription factor with YRPW motif 1; HIFI-α: hypoxia-inducible factor 1, α-subunit; HK2: Hexokinase 2; HSP70: Heat Shock Protein 70; HO: Hydrogen Peroxide; Id2: inhibitor of DNA-binding 2; IGF-1-BP3: Insulin-like growth factor binding protein 3; IL-1β: Interleukin 1 beta; iNOS: inducible nitric oxide synthase; IRS-1: Insulin receptor substrate 1; JNK: c-Jun N-terminal kinases; LY-83583: 6-anilino-5,8-quinolinedione; inhibitor of soluble guanylate cyclase and of cGMP production; Mdm 2/ 4: Mouse double minute 2 homolog (mouse) Mdm4 (humans); mtDNA: mitochondrial DNA; MURF1: Muscle RING-finger protein-1; MyoD: Myogenic differentiation 1; MyoG: myogenin; Nanog: Nanog homeobox; NF-kB: Nuclear factor-κB; NO: nitric oxide; NoxA: phorbol-12-myristate-13-acetate-induced protein 1 (Pmaip1); NRF-1: nuclear respiratory factor 1; Nrf2: Nuclear factor erythroid 2-related factor 2; P21: Cdkn1a cyclin-dependent kinase inhibitor 1A (P21); P38 MAPK: mitogen-activated protein kinases; p53R2: p53 inducible ribonucleotide reductase gene; P66Shc: src homology 2 domain-containing transforming protein C1; PERP: p53 apoptosis effector related to PMP-22; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PGM: phosphoglucomutase; PI3K: Phosphatidylinositol-4,5-bisphosphate 3-kinase; PKCβ: protein kinase c beta; PTEN: phosphatase and tensin homolog; PTIO: 2-phenyl-4, 4, 5, 5,-tetramethylimidazoline-1-oxyl 3-oxide (PTIO) has been used as a nitric oxide (NO) scavenger; Puma: The p53 upregulated modulator of apoptosis; PW1: paternally expressed 3 (Peg3); RNS: Reactive nitrogen species; SIRT1: sirtuin 1; SCO2: cytochrome c oxidase assembly protein; SOD2: superoxide dismutase 2; Tfam: transcription factor A mitochondrial; TIGAR: Trp53 induced glycolysis repulatory phosphatase; TNF-a: tumor necrosis factor a; TRAF2: TNF receptor associated factor 2; TRAIL: type II transmembrane protein.
Topics: Animals; Diet; Exercise; Humans; Muscle, Skeletal; Oxidative Stress; Oxygen; Proto-Oncogene Mas; Radiation Injuries; Tumor Suppressor Protein p53
PubMed: 29298131
DOI: 10.1080/13510002.2017.1416773 -
Sports Medicine (Auckland, N.Z.) May 2015Vascular dysfunction is a precursor to the atherosclerotic cascade, significantly increasing susceptibility to cardiovascular events such as myocardial infarction or... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Vascular dysfunction is a precursor to the atherosclerotic cascade, significantly increasing susceptibility to cardiovascular events such as myocardial infarction or stroke. Previous studies have revealed a strong relationship between vascular function and cardiorespiratory fitness (CRF). Thus, since high-intensity interval training (HIIT) is a potent method of improving CRF, several small randomized trials have investigated the impact on vascular function of HIIT relative to moderate-intensity continuous training (MICT).
OBJECTIVE
The aim of this study was to systematically review the evidence and quantify the impact on vascular function of HIIT compared with MICT.
METHODS
Three electronic databases (PubMed, Embase, and MEDLINE) were searched (until May 2014) for randomized trials comparing the effect of at least 2 weeks of HIIT and MICT on vascular function. HIIT protocols involved predominantly aerobic exercise at a high intensity, interspersed with active or passive recovery periods. We performed a meta-analysis to compare the mean difference in the change in vascular function assessed via brachial artery flow-mediated dilation (FMD) from baseline to post-intervention between HIIT and MICT. The impact of HIIT versus MICT on CRF, traditional cardiovascular disease (CVD) risk factors, and biomarkers associated with vascular function (oxidative stress, inflammation, and insulin resistance) was also reviewed across included studies.
RESULTS
Seven randomized trials, including 182 patients, met the eligibility criteria and were included in the meta-analysis. A commonly used HIIT prescription was four intervals of 4 min (4 × 4 HIIT) at 85-95% of maximum or peak heart rate (HRmax/peak), interspersed with 3 min of active recovery at 60-70% HRmax/peak, three times per week for 12-16 weeks. Brachial artery FMD improved by 4.31 and 2.15% following HIIT and MICT, respectively. This resulted in a significant (p < 0.05) mean difference of 2.26%. HIIT also had a greater tendency than MICT to induce positive effects on secondary outcome measures, including CRF, traditional CVD risk factors, oxidative stress, inflammation, and insulin sensitivity.
CONCLUSION
HIIT is more effective at improving brachial artery vascular function than MICT, perhaps due to its tendency to positively influence CRF, traditional CVD risk factors, oxidative stress, inflammation, and insulin sensitivity. However, the variability in the secondary outcome measures, coupled with the small sample sizes in these studies, limits this finding. Nonetheless, this review suggests that 4 × 4 HIIT, three times per week for at least 12 weeks, is a powerful form of exercise to enhance vascular function.
Topics: Blood Pressure; Body Fat Distribution; Brachial Artery; C-Reactive Protein; Humans; Insulin Resistance; Lipids; Oxidative Stress; Oxygen Consumption; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Physical Fitness; Regional Blood Flow; Resistance Training; Transcription Factors
PubMed: 25771785
DOI: 10.1007/s40279-015-0321-z -
Emerging protein degradation strategies: expanding the scope to extracellular and membrane proteins.Theranostics 2021Classic small molecule inhibitors that directly target pathogenic proteins typically rely on the accessible binding sites to achieve prolonged occupancy and influence... (Review)
Review
Classic small molecule inhibitors that directly target pathogenic proteins typically rely on the accessible binding sites to achieve prolonged occupancy and influence protein functions. The emerging targeted protein degradation (TPD) strategies exemplified by PROteolysis TArgeting Chimeras (PROTACs) are revolutionizing conventional drug discovery modality to target proteins of interest (POIs) that were categorized as "undruggable" before, however, these strategies are limited within intracellular POIs. The novel new degrader technologies such as LYsosome-TArgeting Chimaeras (LYTACs) and Antibody-based PROTACs (AbTACs) have been successfully developed to expand the scope of TPD to extracellular and membrane proteins, fulfilling huge unmet medical needs. Here, we systematically review the currently viable protein degradation strategies, emphasize that LYTACs and AbTACs turn a new avenue for the development of TPD, and highlight the potential challenges and directions in this vibrant field.
Topics: Animals; Cellular Microenvironment; Drug Delivery Systems; Drug Discovery; Humans; Lysosomes; Membrane Proteins; Proteasome Endopeptidase Complex; Proteins; Proteolysis
PubMed: 34373745
DOI: 10.7150/thno.62686 -
Clinical Nutrition (Edinburgh, Scotland) May 2021Trials that assessed the impact of protein supplementation on endurance training adaptations have reported conflicting findings. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Trials that assessed the impact of protein supplementation on endurance training adaptations have reported conflicting findings.
OBJECTIVE
To determine the impact of protein supplementation during chronic endurance training on aerobic capacity, body composition and exercise performance in healthy and clinical populations.
DESIGN
A systematic database search was conducted for randomised controlled trials addressing the effects of protein supplementation during endurance training on aerobic capacity, body composition and exercise performance in PubMed, Embase, Web of Science, and CINAHL. Meta-analyses were performed to outline the overall effects of protein supplementation with all studies containing endurance training components. The effects of endurance training and add-on effects of protein supplementation were evaluated by the meta-analyses with endurance training-focused studies.
RESULTS
Nineteen studies and 1162 participants contributed to the analyses. Compared with the control group, the protein supplementation group demonstrated greater improvements in aerobic capacity measured by mixed peak oxygen uptake (V̇O) and peak workload power (W) (standardised mean difference [SMD] = 0.36, 95% confidence interval [CI]: 0.05 to 0.67), and V̇O (mean difference [MD] = 0.89 mL‧kg‧min, 95% CI: 0.07 to 1.70); had a greater lean mass gain (MD = 0.32 kg, 95% CI: 0.07 to 0.58); and had a greater improvement in time trial performance (MD = -29.1s, 95% CI:-55.3 to -3.0). Secondary analyses showed that, in addition to the substantial improvement in V̇O (MD = 3.67 mL‧kg‧min, 95% CI: 2.32 to 5.03) attributed to endurance training, protein supplementation provided an additional 26.4% gain in V̇O (MD = 0.97 mL‧kg‧min, 95% CI: -0.03 to 1.97).
CONCLUSION
Protein supplementation further increased aerobic capacity, stimulated lean mass gain, and improved time trial performance during chronic endurance training in healthy and clinical populations. PROSPERO REGISTRATION NUMBER: (CRD42020155239).
Topics: Adaptation, Physiological; Body Composition; Dietary Proteins; Dietary Supplements; Endurance Training; Humans; Physical Endurance
PubMed: 33358231
DOI: 10.1016/j.clnu.2020.12.012 -
The Journal of Nutrition Mar 2016Protein intake may influence important health outcomes in later life. (Review)
Review
BACKGROUND
Protein intake may influence important health outcomes in later life.
OBJECTIVE
The objective of this study was to investigate current evidence on the effects of infant formulas and follow-on formulas with different protein concentrations on infants' and children's growth, body composition, and later risk of overweight and obesity.
METHODS
In this systematic review, we searched electronic databases (including MEDLINE, Embase, and the Cochrane Library) up until November 2014 for randomized controlled trials (RCTs). Eligible studies had to include children aged 0-3 y who represented the general population and were fed cow milk-based infant formulas with variations in protein concentration. Control groups received lower-protein cow milk-based formulas (as defined by the authors). The primary outcomes were growth, overweight, obesity, and adiposity. Various time points for outcomes assessment were accepted for inclusion. If possible, a meta-analysis was performed.
RESULTS
Twelve RCTs met our inclusion criteria. Different formula protein concentrations did not affect linear growth other than a transient effect on mean length at 3 mo observed in a meta-analysis of 4 studies (mean difference, - 0.27 cm; 95% CI: -0.52, -0.02). Lower mean weight and weight z scores obtained from the infants fed lower-protein formulas were observed only from 6 to 12 mo of age. Data from one large RCT showed that consumption of a lower-protein infant formula may reduce body mass index at 12 mo of age and later (12 mo, 24 mo, and 6y) and the risk of obesity at 6 y. Effects on body composition remained unclear.
CONCLUSIONS
The current evidence is insufficient for assessing the effects of reducing the protein concentration in infant formulas on long-term outcomes, but, if confirmed, this could be a promising intervention for reducing the risk of overweight and obesity in children. In view of the limited available evidence, more studies replicating effects on long-term health outcomes are needed.
Topics: Animals; Body Composition; Body Mass Index; Body Weight; Child; Child, Preschool; Databases, Factual; Dietary Proteins; Humans; Infant; Infant Formula; Milk; Obesity; Randomized Controlled Trials as Topic; Risk Factors
PubMed: 26865649
DOI: 10.3945/jn.115.223651 -
Ageing Research Reviews Apr 2012Disease-related malnutrition is common, detrimentally affecting the patient and healthcare economy. Although use of high protein oral nutritional supplements (ONS) has... (Meta-Analysis)
Meta-Analysis Review
Disease-related malnutrition is common, detrimentally affecting the patient and healthcare economy. Although use of high protein oral nutritional supplements (ONS) has been recommended to counteract the catabolic effects of disease and to facilitate recovery from illness, there is a lack of systematically obtained evidence to support these recommendations. This systematic review involving 36 randomised controlled trials (RCT) (n=3790) (mean age 74 years; 83% of trials in patients >65 years) and a series of meta-analyses of high protein ONS (>20% energy from protein) demonstrated a range of effects across settings and patient groups in favour of the high protein ONS group. These included reduced complications (odds ratio (OR) 0.68 (95%CI 0.55-0.83), p<0.001, 10 RCT, n=1830); reduced readmissions to hospital (OR 0.59 (95%CI 0.41-0.84), p=0.004, 2 RCT, n=546); improved grip strength (1.76 kg (95%CI 0.36-3.17), p<0.014, 4 RCT, n=219); increased intake of protein (p<0.001) and energy (p<0.001) with little reduction in normal food intake and improvements in weight (p<0.001). There was inadequate information to compare standard ONS (<20% energy from protein) with high protein ONS (>20% energy from protein). The systematic review and meta-analysis provides evidence that high protein supplements produce clinical benefits, with economic implications.
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Dietary Proteins; Dietary Supplements; Energy Intake; Energy Metabolism; Enteral Nutrition; Evidence-Based Medicine; Humans; Malnutrition; Middle Aged; Nutritional Status; Odds Ratio; Recovery of Function; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 22212388
DOI: 10.1016/j.arr.2011.12.008 -
The American Journal of Clinical... Aug 2023Serving whey protein before a meal in order to lower postprandial blood glucose concentrations is known as a premeal. The underlying mechanisms are only partly... (Meta-Analysis)
Meta-Analysis
Whey Protein Premeal Lowers Postprandial Glucose Concentrations in Adults Compared with Water-The Effect of Timing, Dose, and Metabolic Status: a Systematic Review and Meta-analysis.
BACKGROUND
Serving whey protein before a meal in order to lower postprandial blood glucose concentrations is known as a premeal. The underlying mechanisms are only partly understood but may involve stimulation of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and insulin secretion together with a slower gastric emptying rate.
OBJECTIVES
The objective of this systematic review and meta-analysis was to review all randomized clinical trials investigating premeals with whey protein in comparison with a nonactive comparator (control) that evaluated plasma glucose, GLP-1, GIP, insulin, and/or gastric emptying rate. Secondary aims included subgroup analyses on the timing and dose of the premeal together with the metabolic state of the participants [lean, obese, and type 2 diabetes mellitus (T2DM)].
METHODS
We searched EMBASE, CENTRAL, PUBMED, and clinicaltrials.gov and found 16 randomized crossover trials with a total of 244 individuals. The last search was performed on 9 August, 2022.
RESULTS
Whey protein premeals lowered peak glucose concentration by -1.4 mmol/L [-1.9 mmol/L; -0.9 mmol/L], and the area under the curve for glucose was -0.9 standard deviation (SD) [-1.2 SD; -0.6 SD] compared with controls (high certainty). In association with these findings, whey protein premeals elevated GLP-1 (low certainty) and peak insulin (high certainty) concentrations and slowed gastric emptying rate (high certainty) compared with controls. Subgroup analyses showed a more pronounced and prolonged glucose-lowering effect in individuals with T2DM compared with participants without T2DM. The available evidence did not elucidate the role of GIP. The protein dose used varied between 4 and 55 g, and meta-regression analysis showed that the protein dose correlated with the glucose-lowering effects.
CONCLUSIONS
In conclusion, whey protein premeals lower postprandial blood glucose, reduce gastric emptying rate, and increase peak insulin. In addition, whey protein premeals may elevate plasma concentrations of GLP-1. Whey protein premeals may possess clinical potential, but the long-term effects await future clinical trials.
Topics: Humans; Adult; Whey Proteins; Glucagon; Blood Glucose; Diabetes Mellitus, Type 2; Water; Insulin; Glucagon-Like Peptide 1; Gastric Inhibitory Polypeptide; Glucose; Gastric Emptying; Postprandial Period
PubMed: 37536867
DOI: 10.1016/j.ajcnut.2023.05.012 -
The Journal of Pediatrics Aug 2012To examine the influence of protein and energy intakes on protein balance in children receiving mechanical ventilation in the pediatric intensive care unit. (Review)
Review
OBJECTIVE
To examine the influence of protein and energy intakes on protein balance in children receiving mechanical ventilation in the pediatric intensive care unit.
STUDY DESIGN
We hypothesized that higher energy and protein intakes are correlated with positive protein balance. We performed a systematic literature search to identify studies reporting protein balance in children requiring mechanical ventilation. Factors contributing to protein balance, including protein and energy intake, age, illness severity, study design, and feeding routes, were analyzed using a qualitative approach.
RESULTS
Nine studies met the entry criteria and were included in the final analysis. Positive nitrogen balance was reported in 6 of the studies, with a wide range of associated energy and protein intakes. Measures of central tendency for daily energy and protein intakes were significantly correlated with positive protein balance. A minimum intake of 57 kcal/kg/day and 1.5 g protein/kg/day were required to achieve positive protein balance.
CONCLUSION
We found a correlation between higher energy and protein intakes and achievement of positive protein balance in children receiving mechanical ventilation in the pediatric intensive care unit. However, there is a paucity of interventional studies, and a variety of protocols have been used to determine nitrogen balance. Larger clinical trials with uniform methodology are needed to further examine the effect of energy and protein intake on protein balance, lean body mass, and clinical outcomes in children on mechanical ventilation.
Topics: Child; Critical Illness; Dietary Proteins; Energy Intake; Energy Metabolism; Enteral Nutrition; Humans; Intensive Care Units, Pediatric; Nitrogen; Parenteral Nutrition; Proteins; Respiration, Artificial
PubMed: 22402566
DOI: 10.1016/j.jpeds.2012.01.046 -
Journal of Cellular Physiology Jul 2022Pemphigus vulgaris (PV) is a potentially fatal autoimmune blistering disease characterized by cell-cell detachment (or acantholysis) and blister formation. While the... (Review)
Review
Pemphigus vulgaris (PV) is a potentially fatal autoimmune blistering disease characterized by cell-cell detachment (or acantholysis) and blister formation. While the signaling mechanisms that associate with skin/mucosal blistering are being elucidated, specific treatment strategies targeting PV-specific pathomechanisms, particularly kinase signaling, have yet to be established. Hence, the aim of this review was to systematically evaluate molecules in the class of kinases that are essential for acantholysis and blister formation and are therefore candidates for targeted therapy. English articles from PubMed and Scopus databases were searched, and included in vitro, in vivo, and human studies that investigated the role of kinases in PV. We selected studies, extracted data and assessed risk of bias in duplicates and the results were reported according to the methodology outlined by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). The risk of bias assessment was performed on in vivo studies utilizing SYRCLE's risk of bias tool. Thirty-five studies were included that satisfied the pathogenicity criterion of kinases in PV, the vast majority being experimental models that used PV sera (n = 13) and PV-IgG (n = 22). Inhibition of kinase activity (p38MAPK, PKC, TK, c-Src, EGFR, ERK, mTOR, BTK, and CDK2) was achieved mostly by pharmacological means. Overall, we found substantial evidence that kinase inhibition reduced PV-associated phosphorylation events and keratinocyte disassociation, prevented acantholysis, and blocked blister formation. However, the scarce adherence to standardized reporting systems and the experimental protocols/models used did limit the internal and external validity of these studies. In summary, this systematic review highlighted the pathogenic intracellular events mediated by kinases in PV acantholysis and presented kinase signaling as a promising avenue for translational research. In particular, the molecules identified and discussed in this study represent potential candidates for the development of mechanism-based interventions in PV.
Topics: Acantholysis; Autoantibodies; Blister; Humans; Immunoglobulin G; Keratinocytes; Pemphigus; Phosphorylation
PubMed: 35616233
DOI: 10.1002/jcp.30784