scholarly journals Integrated or Independent Actions of Metformin in Target Tissues Underlying Its Current Use and New Possible Applications in the Endocrine and Metabolic Disorder Area

2021 ◽  
Vol 22 (23) ◽  
pp. 13068
Author(s):  
Giovanni Tulipano
Keyword(s):  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Current Knowledge ◽  
Cell Types ◽  
Cellular Level ◽  
Endocrine Tumors ◽  
Age Related ◽  
Distinct Cell ◽  
First Choice ◽  
Integrated Or

Metformin is considered the first-choice drug for type 2 diabetes treatment. Actually, pleiotropic effects of metformin have been recognized, and there is evidence that this drug may have a favorable impact on health beyond its glucose-lowering activity. In summary, despite its long history, metformin is still an attractive research opportunity in the field of endocrine and metabolic diseases, age-related diseases, and cancer. To this end, its mode of action in distinct cell types is still in dispute. The aim of this work was to review the current knowledge and recent findings on the molecular mechanisms underlying the pharmacological effects of metformin in the field of metabolic and endocrine pathologies, including some endocrine tumors. Metformin is believed to act through multiple pathways that can be interconnected or work independently. Moreover, metformin effects on target tissues may be either direct or indirect, which means secondary to the actions on other tissues and consequent alterations at systemic level. Finally, as to the direct actions of metformin at cellular level, the intracellular milieu cooperates to cause differential responses to the drug between distinct cell types, despite the primary molecular targets may be the same within cells. Cellular bioenergetics can be regarded as the primary target of metformin action. Metformin can perturb the cytosolic and mitochondrial NAD/NADH ratio and the ATP/AMP ratio within cells, thus affecting enzymatic activities and metabolic and signaling pathways which depend on redox- and energy balance. In this context, the possible link between pyruvate metabolism and metformin actions is extensively discussed.

scholarly journals Proteomics Analysis of Cellular Network in Human Bone Marrow Reveals Lineage Skewing Towards Megakaryocytes and Decrease in Lymphoid Development upon Aging

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2658-2658
Author(s):  
Anthony D. Ho ◽  
Patrick Horn ◽  
Marco Hennrich ◽  
Samira Jaeger ◽  
Natalie Romanov ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Cellular Level ◽  
Lymphoid Cells ◽  
Down Regulation ◽  
Proteomics Analysis ◽  
Age Related ◽  
Erythroid Precursors ◽  
Related Proteins

Abstract Background: Whereas proteomics analyses at a cellular level have been performed in murine HPC, most proteomics studies on human material have thus far focused on examining human tissues with a mixture of cell types and not at a specific cellular level. Whole proteomics analyses might reveal genuine molecular alterations und mechanisms of aging on human hematopoietic cells. Aim: To identify the age-related molecular changes in human hematopoietic progenitor cells (HPC) as well as in the cellular elements of the human bone marrow niche, we have applied mass spectrometry-based platform for proteomics analysis of this network of bone marrow (BM) cells at a cellular level. The overarching goal is to acquire a systems understanding of the molecular mechanisms involved in aging of human HPC as well as other cellular constituents of the marrow niche, and to combine the cell biological, proteomic, and genetic studies for a better understanding of age-related diseases such as MDS. Methods: In this study, we have simultaneously characterized at the proteomics level HPC as well as the cellular microenvironment in BM from each individual human subject. Cells were harvested from the BM of 69 healthy human subjects [Age Group (AG) 20-29 years: n=19; AG 30-39: n=16; AG 40-49: n=9; AG 50+: N=15]. BM cells were separated for nucleated cells using Ficoll, followed by sorting with specific marker constellations, i.e. HPC (CD34+), lymphoid cells (CD34-/CD45+/SSClow), myeloid precursors (CD34-/CD45med/SSChigh), monocyte-macrophages (CD34-/CD45+/CD14+), erythroid precursors (CD34-/CD45-), and mesenchymal stromal cells (MSC) based on plastic adherence upon culture. Results: In 60 of these 69 healthy subjects we were able to harvest an adequate amount of material from 5 to 6 the aforementioned subsets from the respective individual, yielding altogether 342 samples for proteomics analysis. After digestion (trypsinization), isobaric labelling of peptides (TMT) of appropriate quality was successfully performed in 270 of these 342 samples derived from 69 healthy human subjects. These 270 samples underwent tandem mass-spectrometry analyses. The number of proteins identified were >12,000, covering 65% of the estimated human proteome (HPC: >7,500; Lymphoid cells: >8,500; Myeloid Precursors: >7,500; Mono/Macro: >8,500; Erythroid Precursors: >6,500; and in MSC: >9,000 proteins). We have then focused on the molecular mechanisms, specifically proteomic alterations involved in aging of these 6 cell types. Gene Set Enrichment Analysis (GSEA) using previously defined gene sets specific for common lymphoid progenitors (CLP), bi-potent granulocyte/macrophage progenitors (GMP), and megakaryocyte progenitors (MKP) revealed significant down-regulation of CLP related proteins and significant up-regulation of MKP related proteins in HPC upon aging. The same down-regulation of CLP proteins and up-regulation of MKP proteins were also found in the BM lymphoid cells. Further significant alterations of note are a decrease in cell cycle related proteins upon aging in HPC, lymphoid cells, as well as in MSC, and an increase in GMP related proteins upon aging in lymphoid cells, erythroid precursors and in MSC. Extensive pathway and network analyses are underway. Conclusions: We have for the first time accomplished a multiplex and comprehensive analysis of a community of cells in human BM, comprising HPC and 5 other cell types that constitute the niche and have identified >12,000 proteins in this cellular network. Proteomics analyses have demonstrated a significant down-regulation of CLP related proteins in human HPC and in marrow lymphoid cells, as well as an up-regulation of MKP in all the cell types tested upon aging. Of note is also a decrease in cell cycle related proteins with age. This study has thus provided evidence that lineage skewing towards megakaryocytic and decrease in lymphoid development upon aging occur in human HPC as well as in other human BM cells. Disclosures No relevant conflicts of interest to declare.

scholarly journals Glucocorticoid Receptor β (GRβ): Beyond Its Dominant-Negative Function

2021 ◽  
Vol 22 (7) ◽  
pp. 3649
Author(s):  
Patricia Ramos-Ramírez ◽  
Omar Tliba
Keyword(s):  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Cell Communication ◽  
Cell Types ◽  
The Body ◽  
Dominant Negative ◽  
Negative Effects ◽  
Independent Manner ◽  
Distinct Cell ◽  
Induced Apoptosis

Glucocorticoids (GCs) act via the GC receptor (GR), a receptor ubiquitously expressed in the body where it drives a broad spectrum of responses within distinct cell types and tissues, which vary in strength and specificity. The variability of GR-mediated cell responses is further extended by the existence of GR isoforms, such as GRα and GRβ, generated through alternative splicing mechanisms. While GRα is the classic receptor responsible for GC actions, GRβ has been implicated in the impairment of GRα-mediated activities. Interestingly, in contrast to the popular belief that GRβ actions are restricted to its dominant-negative effects on GRα-mediated responses, GRβ has been shown to have intrinsic activities and “directly” regulates a plethora of genes related to inflammatory process, cell communication, migration, and malignancy, each in a GRα-independent manner. Furthermore, GRβ has been associated with increased cell migration, growth, and reduced sensitivity to GC-induced apoptosis. We will summarize the current knowledge of GRβ-mediated responses, with a focus on the GRα-independent/intrinsic effects of GRβ and the associated non-canonical signaling pathways. Where appropriate, potential links to airway inflammatory diseases will be highlighted.

scholarly journals Lysosomal Exocytosis, Exosome Release and Secretory Autophagy: The Autophagic- and Endo-Lysosomal Systems Go Extracellular

2020 ◽  
Vol 21 (7) ◽  
pp. 2576 ◽  
Author(s):  
Sandra Buratta ◽  
Brunella Tancini ◽  
Krizia Sagini ◽  
Federica Delo ◽  
Elisabetta Chiaradia ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Cell Communication ◽  
Lysosomal Storage ◽  
Cellular Processes ◽  
Age Related ◽  
Extracellular Release ◽  
A Cell ◽  
Endosomal System

Beyond the consolidated role in degrading and recycling cellular waste, the autophagic- and endo-lysosomal systems play a crucial role in extracellular release pathways. Lysosomal exocytosis is a process leading to the secretion of lysosomal content upon lysosome fusion with plasma membrane and is an important mechanism of cellular clearance, necessary to maintain cell fitness. Exosomes are a class of extracellular vesicles originating from the inward budding of the membrane of late endosomes, which may not fuse with lysosomes but be released extracellularly upon exocytosis. In addition to garbage disposal tools, they are now considered a cell-to-cell communication mechanism. Autophagy is a cellular process leading to sequestration of cytosolic cargoes for their degradation within lysosomes. However, the autophagic machinery is also involved in unconventional protein secretion and autophagy-dependent secretion, which are fundamental mechanisms for toxic protein disposal, immune signalling and pathogen surveillance. These cellular processes underline the crosstalk between the autophagic and the endosomal system and indicate an intersection between degradative and secretory functions. Further, they suggest that the molecular mechanisms underlying fusion, either with lysosomes or plasma membrane, are key determinants to maintain cell homeostasis upon stressing stimuli. When they fail, the accumulation of undigested substrates leads to pathological consequences, as indicated by the involvement of autophagic and lysosomal alteration in human diseases, namely lysosomal storage disorders, age-related neurodegenerative diseases and cancer. In this paper, we reviewed the current knowledge on the functional role of extracellular release pathways involving lysosomes and the autophagic- and endo-lysosomal systems, evaluating their implication in health and disease.

scholarly journals Do Nutritional Supplements Have a Role in Age Macular Degeneration Prevention?

2014 ◽  
Vol 2014 ◽  
pp. 1-15 ◽  
Author(s):  
Maria D. Pinazo-Durán ◽  
Francisco Gómez-Ulla ◽  
Luis Arias ◽  
Javier Araiz ◽  
Ricardo Casaroli-Marano ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Scientific Evidence ◽  
Experimental Studies ◽  
Beta Carotene ◽  
Dietary Intakes ◽  
Omega 3 ◽  
Age Related ◽  
Disease Study

Purpose. To review the proposed pathogenic mechanisms of age macular degeneration (AMD), as well as the role of antioxidants (AOX) and omega-3 fatty acids (ω-3) supplements in AMD prevention.Materials and Methods. Current knowledge on the cellular/molecular mechanisms of AMD and the epidemiologic/experimental studies on the effects of AOX andω-3 were addressed all together with the scientific evidence and the personal opinion of professionals involved in the Retina Group of the OFTARED (Spain).Results. High dietary intakes ofω-3 and macular pigments lutein/zeaxanthin are associated with lower risk of prevalence and incidence in AMD. The Age-Related Eye Disease study (AREDS) showed a beneficial effect of high doses of vitamins C, E, beta-carotene, and zinc/copper in reducing the rate of progression to advanced AMD in patients with intermediate AMD or with one-sided late AMD. The AREDS-2 study has shown that lutein and zeaxanthin may substitute beta-carotene because of its potential relationship with increased lung cancer incidence.Conclusion. Research has proved that elder people with poor diets, especially with low AOX andω-3 micronutrients intake and subsequently having low plasmatic levels, are more prone to developing AMD. Micronutrient supplementation enhances antioxidant defense and healthy eyes and might prevent/retard/modify AMD.

scholarly journals Thrombospondin-1 in maladaptive aging responses: a concept whose time has come

2020 ◽  
Vol 319 (1) ◽  
pp. C45-C63
Author(s):  
Jeffrey S. Isenberg ◽  
David D. Roberts
Keyword(s):  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Genotoxic Stress ◽  
Cell Types ◽  
Cellular Tissue ◽  
Therapeutic Agents ◽  
Age Related ◽  
Organ Systems ◽  
Age Dependent ◽  
Thrombospondin 1

Numerous age-dependent alterations at the molecular, cellular, tissue and organ systems levels underlie the pathophysiology of aging. Herein, the focus is upon the secreted protein thrombospondin-1 (TSP1) as a promoter of aging and age-related diseases. TSP1 has several physiological functions in youth, including promoting neural synapse formation, mediating responses to ischemic and genotoxic stress, minimizing hemorrhage, limiting angiogenesis, and supporting wound healing. These acute functions of TSP1 generally require only transient expression of the protein. However, accumulating basic and clinical data reinforce the view that chronic diseases of aging are associated with accumulation of TSP1 in the extracellular matrix, which is a significant maladaptive contributor to the aging process. Identification of the relevant cell types that chronically produce and respond to TSP1 and the molecular mechanisms that mediate the resulting maladaptive responses could direct the development of therapeutic agents to delay or revert age-associated maladies.

scholarly journals Reciprocal expression of 17α-hydroxylase-C17,20-lyase and aromatase cytochrome P450 during bovine trophoblast differentiation: a two-cell system drives placental oestrogen synthesis

Reproduction ◽  
2006 ◽  
Vol 131 (4) ◽  
pp. 669-679 ◽  
Author(s):  
G Schuler ◽  
G R Özalp ◽  
B Hoffmann ◽  
N Harada ◽  
P Browne ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Cell Types ◽  
Staining Intensity ◽  
Giant Cells ◽  
Cell System ◽  
Cellular Level ◽  
Specific Staining ◽  
Cytoplasmic Staining ◽  
Distinct Cell ◽  
Trophoblast Giant Cells

No definitive information is yet available on the steroidogenic capacity of the two morphologically distinct cell types forming the bovine trophoblast, the uninucleated trophoblast cells (UTCs) and the trophoblast giant cells (TGCs). Hence, in order to localise 17α-hydroxylase-C17,20-lyase (P450c17) on a cellular level and to monitor its expression as a function of gestational age, placentomes from pregnant (days 80–284; n = 19), prepartal (days 273–282; 24–36 h prior to the onset of labour; n = 3) and parturient cows (n = 5) were immunostained for P450c17 using an antiserum against the recombinant bovine enzyme. At all stages investigated, P450c17 was exclusively found in the UTCs of chorionic villi (CV), where staining was ubiquitous between days 80 and 160, but was largely restricted to primary CV and the branching sites of secondary CV between days 160 and 240. Thereafter, a distinct ubiquitous staining reoccurred in the UTCs of all CV in late pregnant, prepartal and parturient animals. Using an antiserum against human aromatase cytochrome P450 (P450arom), specific cytoplasmic staining was observed in TGCs. In placentomes from pregnant cows, staining intensity was higher in mature compared with immature TGCs and was more pronounced in the trophoblast covering big stem villi compared with the trophoblast at other sites of the villous tree. In placentomes of a parturient cow, specific staining was only found in mature TGCs that survived the normal, but substantial, prepartal decline in TGC numbers. These results clearly showed that bovine UTCs and TGCs exhibit different steroidogenic capacities, constituting a ‘two-cell’ organisation for oestrogen synthesis. P450c17 expression appears to be quickly down-regulated and P450arom is up-regulated when UTCs enter the TGC differentiation pathway.

The complexity and evolution of the plastid-division machinery

2010 ◽  
Vol 38 (3) ◽  
pp. 783-788 ◽  
Author(s):  
Jodi Maple ◽  
Simon Geir Møller
Keyword(s):  
Molecular Mechanisms ◽  
Environmental Changes ◽  
Cell Types ◽  
Cellular Level ◽  
Plastid Division ◽  
Bacterial Cell Division ◽  
Metabolic Functions ◽  
Photosynthetic Eukaryotes ◽  
Metabolic Output ◽  
Host Nucleus

Plastids are vital organelles, fulfilling important metabolic functions that greatly influence plant growth and productivity. In order to both regulate and harness the metabolic output of plastids, it is vital that the process of plastid division is carefully controlled. This is essential, not only to ensure persistence in dividing plant cells and that optimal numbers of plastids are obtained in specialized cell types, but also to allow the cell to act in response to developmental signals and environmental changes. How this control is exerted by the host nucleus has remained elusive. Plastids evolved by endosymbiosis and during the establishment of a permanent endosymbiosis they retained elements of the bacterial cell-division machinery. Through evolution the photosynthetic eukaryotes have increased dramatically in complexity, from single-cell green algae to multicellular non-vascular and vascular plants. Reflected with this is an increasing complexity of the division machinery and recent findings also suggest increasing complexity in the molecular mechanisms used by the host cell to control the process of plastid division. In the present paper, we explore the current understanding of the process of plastid division at the molecular and cellular level, with particular respect to the evolution of the division machinery and levels of control exerted on the process.

scholarly journals Mitochondrial Heterogeneity in the Brain at the Cellular Level

1998 ◽  
Vol 18 (3) ◽  
pp. 231-237 ◽  
Author(s):  
Ursula Sonnewald ◽  
Leif Hertz ◽  
Arne Schousboe
Keyword(s):  
Amino Acid ◽  
Current Knowledge ◽  
Cell Types ◽  
Cellular Level ◽  
Mitochondrial Structure ◽  
Cell Type Specific ◽  
Mitochondrial Heterogeneity ◽  
Specific Tissue ◽  
And Function ◽  
The Brain

Classically, compartmentation of glutamate metabolism in the brain is associated with the fact that neurons and glia exhibit distinct differences with regard to metabolism of this amino acid. The recent use of 13C-labeled compounds to study this metabolism in conjunction with the availability of cell type-specific tissue culture modes has led to the notion that such compartmentation may even be present in individual cell types, neurons as well as glia. To better understand and explain this, it is proposed that mitochondrial heterogeneity may exist resulting in tricarboxylic acid cycles with different properties regarding cycling rates and ratio as well as coupling to amino acid biosynthesis, primarily involving glutamate and aspartate. These hypotheses are evaluated in the light of current knowledge about mitochondrial structure and function.

scholarly journals The islet ghrelin cell

2013 ◽  
Vol 52 (1) ◽  
pp. R35-R49 ◽  
Author(s):  
Nils Wierup ◽  
Frank Sundler ◽  
R Scott Heller
Keyword(s):  
Molecular Mechanisms ◽  
Developmental Stages ◽  
Developmental Regulation ◽  
Genetic Regulation ◽  
Cell Types ◽  
Human Islets ◽  
Histochemical Staining ◽  
Pancreatic Tumours ◽  
Age Related ◽  
Staining Methods

The islets of Langerhans are key regulators of glucose homeostasis and have been known as a structure for almost one and a half centuries. During the twentieth century several different cell types were described in the islets of different species and at different developmental stages. Six cell types with identified hormonal product have been described so far by the use of histochemical staining methods, transmission electron microscopy, and immunohistochemistry. Thus, glucagon-producing α-cells, insulin-producing β-cells, somatostatin-producing δ-cells, pancreatic polypeptide-producing PP-cells, serotonin-producing enterochromaffin-cells, and gastrin-producing G-cells have all been found in the mammalian pancreas at least at some developmental stage. Species differences are at hand and age-related differences are also to be considered. Eleven years ago a novel cell type, the ghrelin cell, was discovered in the human islets. Subsequent studies have shown the presence of islet ghrelin cells in several animals, including mouse, rat, gerbils, and fish. The developmental regulation of ghrelin cells in the islets of mice has gained a lot of interest and several studies have added important pieces to the puzzle of molecular mechanisms and the genetic regulation that lead to differentiation into mature ghrelin cells. A body of evidence has shown that ghrelin is an insulinostatic hormone, and the potential for blockade of ghrelin signalling as a therapeutic avenue for type 2 diabetes is intriguing. Furthermore, ghrelin-expressing pancreatic tumours have been reported and ghrelin needs to be taken into account when diagnosing pancreatic tumours. In this review article, we summarise the knowledge about islet ghrelin cells obtained so far.

scholarly journals Characterization of primary cilia features reveal cell-type specific variability in in vitro models of osteogenic and chondrogenic differentiation

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9799
Author(s):  
Priyanka Upadhyai ◽  
Vishal Singh Guleria ◽  
Prajna Udupa
Keyword(s):  
Cell Lines ◽  
Chondrogenic Differentiation ◽  
Primary Cilia ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Cell Types ◽  
Treatment Modalities ◽  
Cell Type ◽  
Cell Type Specific

Primary cilia are non-motile sensory antennae present on most vertebrate cell surfaces. They serve to transduce and integrate diverse external stimuli into functional cellular responses vital for development, differentiation and homeostasis. Ciliary characteristics, such as length, structure and frequency are often tailored to distinct differentiated cell states. Primary cilia are present on a variety of skeletal cell-types and facilitate the assimilation of sensory cues to direct skeletal development and repair. However, there is limited knowledge of ciliary variation in response to the activation of distinct differentiation cascades in different skeletal cell-types. C3H10T1/2, MC3T3-E1 and ATDC5 cells are mesenchymal stem cells, preosteoblast and prechondrocyte cell-lines, respectively. They are commonly employed in numerous in vitro studies, investigating the molecular mechanisms underlying osteoblast and chondrocyte differentiation, skeletal disease and repair. Here we sought to evaluate the primary cilia length and frequencies during osteogenic differentiation in C3H10T1/2 and MC3T3-E1 and chondrogenic differentiation in ATDC5 cells, over a period of 21 days. Our data inform on the presence of stable cilia to orchestrate signaling and dynamic alterations in their features during extended periods of differentiation. Taken together with existing literature these findings reflect the occurrence of not only lineage but cell-type specific variation in ciliary attributes during differentiation. These results extend our current knowledge, shining light on the variabilities in primary cilia features correlated with distinct differentiated cell phenotypes. It may have broader implications in studies using these cell-lines to explore cilia dependent cellular processes and treatment modalities for skeletal disorders centered on cilia modulation.

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