scholarly journals Does Calorie Restriction Modulate Inflammaging via FoxO Transcription Factors?

Nutrients ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1959
Author(s):  
Sang-Eun Kim ◽  
Ryoichi Mori ◽  
Isao Shimokawa
Keyword(s):  
Transcription Factors ◽  
Calorie Restriction ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Functional Decline ◽  
Cell Lineage ◽  
Myeloid Cell ◽  
The Body ◽  
Pyrin Domain ◽  
Foxo Transcription Factors

Calorie restriction (CR) has been shown to extend lifespan and retard aging-related functional decline in animals. Previously, we found that the anti-neoplastic and lifespan-extending effects of CR in mice are regulated by forkhead box O transcription factors (FoxO1 and FoxO3), located downstream of growth hormone (GH)–insulin-like growth factor (IGF)-1 signaling, in an isoform-specific manner. Inflammaging is a term coined to represent that persistent low-level of inflammation underlies the progression of aging and related diseases. Attenuation of inflammaging in the body may underlie the effects of CR. Recent studies have also identified cellular senescence and activation of the nucleotide-binding domain, leucine-rich-containing family, pyrin-domain-containing-3 (NLRP3) inflammasome as causative factors of inflammaging. In this paper, we reviewed the current knowledge of the molecular mechanisms linking the effects of CR with the formation of inflammasomes, particularly focusing on possible relations with FoxO3. Inflammation in the brain that affects adult neurogenesis and lifespan was also reviewed as evidence of inflammaging. A recent progress of microRNA research was described as regulatory circuits of initiation and propagation of inflammaging. Finally, we briefly introduced our preliminary results obtained from the mouse models, in which Foxo1 and Foxo3 genes were conditionally knocked out in the myeloid cell lineage.

Molecular mechanisms of life- and health-span extension: role of calorie restriction and exercise intervention

2007 ◽  
Vol 32 (5) ◽  
pp. 954-966 ◽  
Author(s):  
Christy S. Carter ◽  
Tim Hofer ◽  
Arnold Y. Seo ◽  
Christian Leeuwenburgh
Keyword(s):  
Life Span ◽  
Calorie Restriction ◽  
Aging Process ◽  
Molecular Mechanisms ◽  
Geriatric Medicine ◽  
Functional Decline ◽  
Intervention Strategies ◽  
Health Span ◽  
Structural Deterioration ◽  
Age Related

The aging process results in a gradual and progressive structural deterioration of biomolecular and cellular compartments and is associated with many pathological conditions, including cardiovascular disease, stroke, Alzheimer’s disease, osteoporosis, sarcopenia, and liver dysfunction. Concomitantly, each of these conditions is associated with progressive functional decline, loss of independence, and ultimately disability. Because disabled individuals require care in outpatient or home care settings, and in light of the social, emotional, and fiscal burden associated with caring for an ever-increasing elderly population, research in geriatric medicine has recently focused on the biological mechanisms that are involved in the progression towards functional decline and disability to better design treatment and intervention strategies. Although not completely understood, the mechanisms underlying the aging process may partly involve inflammatory processes, oxidative damage, mitochondrial dysfunction, and apoptotic tissue degeneration. These hypotheses are based on epidemiological evidence and data from animal models of aging, as well as interventional studies. Findings from these studies have identified possible strategies to decrease the incidence of age-related diseases and delay the aging process. For example, lifelong exercise is known to extend mean life-span, whereas calorie restriction (CR) increases both mean and maximum life-span in a variety of species. Optimal application of these intervention strategies in the elderly may positively affect health-related outcomes and possibly longevity. Therefore, the scope of this article is to (i) provide an interpretation of various theories of aging from a “health-span” perspective; (ii) describe interventional testing in animals (CR and exercise); and (iii) provide a translational interpretation of these data.

scholarly journals AKT signaling restrains tumor suppressive functions of FOXO transcription factors and GSK3 kinase in multiple myeloma

2020 ◽  
Vol 4 (17) ◽  
pp. 4151-4164
Author(s):  
Timon A. Bloedjes ◽  
Guus de Wilde ◽  
Chiel Maas ◽  
Eric Eldering ◽  
Richard J. Bende ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Transcription Factors ◽  
Glycogen Synthase ◽  
Gene Activation ◽  
Prognostic Significance ◽  
Myeloid Cell ◽  
Akt Signaling ◽  
Cycle Arrest ◽  
Foxo Transcription Factors ◽  
Molecular Aspects

Abstract The phosphatidylinositide-3 kinases and the downstream mediator AKT drive survival and proliferation of multiple myeloma (MM) cells. AKT signaling is active in MM and has pleiotropic effects; however, the key molecular aspects of AKT dependency in MM are not fully clear. Among the various downstream AKT targets are the Forkhead box O (FOXO) transcription factors (TFs) and glycogen synthase kinase 3 (GSK3), which are negatively regulated by AKT signaling. Here we show that abrogation of AKT signaling in MM cells provokes cell death and cell cycle arrest, which crucially depends on both FOXO TFs and GSK3. Based on gene expression profiling, we defined a FOXO-repressed gene set that has prognostic significance in a large cohort of patients with MM, indicating that AKT-mediated gene activation is associated with inferior overall survival. We further show that AKT signaling stabilizes the antiapoptotic myeloid cell leukemia 1 (MCL1) protein by inhibiting FOXO- and GSK3-mediated MCL1 turnover. In concordance, abrogation of AKT signaling greatly sensitized MM cells for an MCL1-targeting BH3-mimetic, which is currently in clinical development. Taken together, our results indicate that AKT activity is required to restrain the tumor-suppressive functions of FOXO and GSK3, thereby stabilizing the antiapoptotic protein MCL1 in MM. These novel insights into the role of AKT in MM pathogenesis and MCL1 regulation provide opportunities to improve targeted therapy for patients with MM.

scholarly journals Does Ceruloplasmin Defend Against Neurodegenerative Diseases?

2019 ◽  
Vol 17 (6) ◽  
pp. 539-549 ◽  
Author(s):  
Bo Wang ◽  
Xiao-Ping Wang
Keyword(s):  
Neurodegenerative Diseases ◽  
Iron Metabolism ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Genetic Disorder ◽  
Protective Role ◽  
The Body ◽  
Iron Accumulation ◽  
Ferroxidase Activity ◽  
Abnormal Metabolism

Ceruloplasmin (CP) is the major copper transport protein in plasma, mainly produced by the liver. Glycosylphosphatidylinositol-linked CP (GPI-CP) is the predominant form expressed in astrocytes of the brain. A growing body of evidence has demonstrated that CP is an essential protein in the body with multiple functions such as regulating the homeostasis of copper and iron ions, ferroxidase activity, oxidizing organic amines, and preventing the formation of free radicals. In addition, as an acute-phase protein, CP is induced during inflammation and infection. The fact that patients with genetic disorder aceruloplasminemia do not suffer from tissue copper deficiency, but rather from disruptions in iron metabolism shows essential roles of CP in iron metabolism rather than copper. Furthermore, abnormal metabolism of metal ions and oxidative stress are found in other neurodegenerative diseases, such as Wilson’s disease, Alzheimer’s disease and Parkinson’s disease. Brain iron accumulation and decreased activity of CP have been shown to be associated with neurodegeneration. We hypothesize that CP may play a protective role in neurodegenerative diseases. However, whether iron accumulation is a cause or a result of neurodegeneration remains unclear. Further research on molecular mechanisms is required before a consensus can be reached regarding a neuroprotective role for CP in neurodegeneration. This review article summarizes the main physiological functions of CP and the current knowledge of its role in neurodegenerative diseases.

FOXO transcription factors are required for normal somatotrope function and growth

Endocrinology ◽  
2021 ◽  
Author(s):  
Caitlin E Stallings ◽  
Jyoti Kapali ◽  
Brian W Evans ◽  
Stacey R McGee ◽  
Buffy S Ellsworth
Keyword(s):  
Growth Hormone ◽  
Transcription Factors ◽  
Pituitary Gland ◽  
Molecular Mechanisms ◽  
Pituitary Growth Hormone ◽  
Related Family ◽  
Foxo Transcription Factors ◽  
Gland Function ◽  
And Function ◽  
Free Serum

Abstract Understanding the molecular mechanisms underlying pituitary organogenesis and function is essential for improving therapeutics and molecular diagnoses for hypopituitarism. We previously found that deletion of the forkhead factor, Foxo1, in the pituitary gland early in development delays somatotrope differentiation. While these mice grow normally, they have reduced growth hormone expression and free serum IGF1 levels, suggesting a defect in somatotrope function. FOXO factors show functional redundancy in other tissues, so we deleted both Foxo1 and its closely related family member, Foxo3, from the primordial pituitary. We find that this results in a significant reduction in growth. Consistent with this, male and female mice in which both genes have been deleted in the pituitary gland (dKO) exhibit reduced pituitary growth hormone expression and serum IGF1 levels. Expression of the somatotrope differentiation factor, Neurod4, is reduced in these mice. This suggests a mechanism underlying proper somatotrope function is the regulation of Neurod4 expression by FOXO factors. Additionally, dKO mice have reduced Lhb expression and females also have reduced Fshb and Prl expression. These studies reveal FOXO transcription factors as important regulators of pituitary gland function.

Activation Functions 1 and 2 of Nuclear Receptors: Molecular Strategies for Transcriptional Activation

2003 ◽  
Vol 17 (10) ◽  
pp. 1901-1909 ◽  
Author(s):  
Anette Wärnmark ◽  
Eckardt Treuter ◽  
Anthony P. H. Wright ◽  
Jan-Åke Gustafsson
Keyword(s):  
Transcription Factors ◽  
Rna Polymerase Ii ◽  
Nuclear Receptors ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Current Knowledge ◽  
Preinitiation Complex ◽  
Activation Domains ◽  
Terminal Domain

Abstract Nuclear receptors (NRs) comprise a family of ligand inducible transcription factors. To achieve transcriptional activation of target genes, DNA-bound NRs directly recruit general transcription factors (GTFs) to the preinitiation complex or bind intermediary factors, so-called coactivators. These coactivators often constitute subunits of larger multiprotein complexes that act at several functional levels, such as chromatin remodeling, enzymatic modification of histone tails, or modulation of the preinitiation complex via interactions with RNA polymerase II and GTFs. The binding of NR to coactivators is often mediated through one of its activation domains. Many NRs have at least two activation domains, the ligand-independent activation function (AF)-1, which resides in the N-terminal domain, and the ligand-dependent AF-2, which is localized in the C-terminal domain. In this review, we summarize and discuss current knowledge regarding the molecular mechanisms of AF-1- and AF-2-mediated gene activation, focusing on AF-1 and AF-2 conformation and coactivator binding.

Epigenetic control of hematopoiesis: the PU.1 chromatin connection

2014 ◽  
Vol 395 (11) ◽  
pp. 1265-1274 ◽  
Author(s):  
Boet van Riel ◽  
Frank Rosenbauer
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Current Knowledge ◽  
Dna Methyltransferases ◽  
Chromatin Remodelers ◽  
Cell Lineages ◽  
Protein Partners ◽  
Genome Wide

Abstract Purine-rich box1 (PU.1) is a transcription factor that not only has a key role in the development of most hematopoietic cell lineages but also in the suppression of leukemia. To exert these functions, PU.1 can cross-talk with multiple different proteins by forming complexes in order to activate or repress transcription. Among its protein partners are chromatin remodelers, DNA methyltransferases, and a number of other transcription factors with important roles in hematopoiesis. While a great deal of knowledge has been acquired about PU.1 function over the years, it was the development of novel genome-wide technologies, which boosted our understanding of how PU.1 acts on the chromatin to drive its repertoire of target genes. This review summarizes current knowledge and ideas of molecular mechanisms by which PU.1 controls hematopoiesis and suppresses leukemia.

scholarly journals Hematopoietic Differentiation of Human Pluripotent Stem Cells: HOX and GATA Transcription Factors as Master Regulators

2019 ◽  
Vol 20 (6) ◽  
pp. 438-452 ◽  
Author(s):  
Khaled Alsayegh ◽  
Lorena V. Cortés-Medina ◽  
Gerardo Ramos-Mandujano ◽  
Heba Badraiq ◽  
Mo Li
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Pluripotent Stem Cells ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
The Body ◽  
Hematopoietic Differentiation ◽  
Hematopoietic Stem ◽  
Master Regulators ◽  
Wide Range

Numerous human disorders of the blood system would directly or indirectly benefit from therapeutic approaches that reconstitute the hematopoietic system. Hematopoietic stem cells (HSCs), either from matched donors or ex vivo manipulated autologous tissues, are the most used cellular source of cell therapy for a wide range of disorders. Due to the scarcity of matched donors and the difficulty of ex vivo expansion of HSCs, there is a growing interest in harnessing the potential of pluripotent stem cells (PSCs) as a de novo source of HSCs. PSCs make an ideal source of cells for regenerative medicine in general and for treating blood disorders in particular because they could expand indefinitely in culture and differentiate to any cell type in the body. However, advancement in deriving functional HSCs from PSCs has been slow. This is partly due to an incomplete understanding of the molecular mechanisms underlying normal hematopoiesis. In this review, we discuss the latest efforts to generate human PSC (hPSC)-derived HSCs capable of long-term engraftment. We review the regulation of the key transcription factors (TFs) in hematopoiesis and hematopoietic differentiation, the Homeobox (HOX) and GATA genes, and the interplay between them and microRNAs. We also propose that precise control of these master regulators during the course of hematopoietic differentiation is key to achieving functional hPSC-derived HSCs.

scholarly journals The Interplay Between Chromatin Architecture and Lineage-Specific Transcription Factors and the Regulation of Rag Gene Expression

2021 ◽  
Vol 12 ◽  
Author(s):  
Kazuko Miyazaki ◽  
Masaki Miyazaki
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Specific Gene ◽  
Cell Type ◽  
Cell Fate Decisions ◽  
Chromatin Architecture ◽  
Cell Type Specific

Cell type-specific gene expression is driven through the interplay between lineage-specific transcription factors (TFs) and the chromatin architecture, such as topologically associating domains (TADs), and enhancer-promoter interactions. To elucidate the molecular mechanisms of the cell fate decisions and cell type-specific functions, it is important to understand the interplay between chromatin architectures and TFs. Among enhancers, super-enhancers (SEs) play key roles in establishing cell identity. Adaptive immunity depends on the RAG-mediated assembly of antigen recognition receptors. Hence, regulation of the Rag1 and Rag2 (Rag1/2) genes is a hallmark of adaptive lymphoid lineage commitment. Here, we review the current knowledge of 3D genome organization, SE formation, and Rag1/2 gene regulation during B cell and T cell differentiation.

Comprehensive Network Analysis of the Molecular Mechanisms Associated with Sorafenib Resistance in Hepatocellular Carcinoma

2019 ◽  
Author(s):  
Xiang Cui ◽  
Chao Li ◽  
Chunshan Wei ◽  
Guangdong Tong ◽  
Yufeng Xing
Keyword(s):  
Hepatocellular Carcinoma ◽  
Transcription Factors ◽  
Differentially Expressed Genes ◽  
Gene Networks ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Differential Expression Analysis ◽  
Diagnostic Value ◽  
The Body ◽  
Differentially Expressed

Abstract Background: This research aimed to investigate the potential molecular mechanism of sorafenib resistance to hepatocellular carcinoma (HCC). Methods: Differential expression analysis were performed to identified differentially expressed genes (DEGs) in sorafenib resistant HCC. Then, a series of bioinformatic analysis were performed to explore the potential crucial molecules in sorafenib resistant HCC. For example, gene function annotation, pivot regulators prediction, ROC analysis and survival analysis. Results: There were 827 differentially expressed genes were identified. Moreover, most of the differentially expressed genes are involved in immune and inflammatory-related functions and signaling pathways. Also, 18 transcription factors were predicted to regulate the transcription factors of differentially expressed genes, which play an essential role in the regulation of dysfunctional gene networks. In target genes of transcription factors, CDK1 and CDKN1A have high diagnostic value in the resistance of hepatocellular carcinoma to sorafenib. Conclusions: TAPBP has the strongest correlation with drug resistance of hepatocellular carcinoma and the highest diagnostic efficiency. In addition, CDK1 and CDKN1A have high diagnostic value in the resistance of hepatocellular carcinoma to sorafenib. Overall, our analysis shows that a large number of gene disorders occur during the development of resistance to sorafenib in hepatocellular carcinoma, and they are associated with immune and inflammatory reactions in the body. These results provide critical theoretical references for the pathogenesis and diagnosis of sorafenib resistance.

scholarly journals The emerging role of FOXO transcription factors in pancreatic β cells

2007 ◽  
Vol 193 (2) ◽  
pp. 195-207 ◽  
Author(s):  
Dominique A Glauser ◽  
Werner Schlegel
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Cell Mass ◽  
Endocrine Function ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Foxo Transcription Factors

FOXO transcription factors critically control fundamental cellular processes, including metabolism, cell differentiation, cell cycle arrest, DNA repair, and other reactions to cellular stress. FOXO factors sense the balance between stimuli promoting growth and differentiation versus stress stimuli signaling damage. Integrated through the FOXO system, these divergent stimuli decide on cell fate, a choice between proliferation, differentiation, or apoptosis. In pancreatic β cells, most recent evidence highlights complex FOXO-dependent responses to glucose, insulin, or other growth factors, which include regulatory feedback. In the short term, FOXO-dependent mechanisms help β cells to accomplish their endocrine function, and may increase their resistance to oxidative stress due to transient hyperglycemia. In the long term, FOXO-dependent responses lead to the adaptation of β cell mass, conditioning the future ability of the organism to produce insulin and cope with changes in fuel abundance. FOXO emerges as a key factor for the maintenance of a functional endocrine pancreas and represents an interesting element in the development of therapeutic approaches to treat diabetes. This review on the role of FOXO transcription factors in pancreatic β cells has three parts. In Part I, FOXO transcription factors will be presented in general: structure, molecular mechanisms of regulation, cellular functions, and physiological roles. Part II will focus on specific data about FOXO factors in pancreatic β cells. Lastly in Part III, it will be attempted to combine general and β cell-specific knowledge with the aim to envisage globally the role of FOXO factors in β cell-linked physiology and disease.

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