Beneficial effects of spermidine on cardiovascular health and longevity suggest a cell type-specific import of polyamines by cardiomyocytes

2018 ◽  
Vol 47 (1) ◽  
pp. 265-272 ◽  
Author(s):  
Bengt-Olof Nilsson ◽  
Lo Persson
Keyword(s):  
Cardiovascular Health ◽  
In Vivo Studies ◽  
Special Focus ◽  
Cell Type ◽  
Excitable Cells ◽  
Beneficial Effects ◽  
A Cell ◽  
Cell Type Specific ◽  
Stimulation Of

Abstract Recent and exciting in vivo studies show that supplementation with the polyamine spermidine (Spd) is cardioprotective and prolongs lifespan in both mice and humans. The mechanisms behind Spd-induced cardioprotection are supposed to involve Spd-evoked stimulation of autophagy, mitophagy and mitochondrial respiration and improved the mechano-elastical function of cardiomyocytes. Although cellular uptake of Spd was not characterized, these results suggest that Spd is imported by the cardiomyocytes and acts intracellularly. In the light of these new and thrilling data, we discuss in the present review cellular polyamine import with a special focus on mechanisms that may be relevant for Spd uptake by electrically excitable cells such as cardiomyocytes.

Gene therapy can target mutations such as BRAF, which have been shown to make tumors more susceptible to autophagy suppression

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Signaling Pathways ◽  
Chemotherapy Resistance ◽  
Effective Strategy ◽  
Cell Type ◽  
Normal Cells ◽  
A Cell ◽  
Cell Type Specific ◽  
Catabolic Process ◽  
Specific Impact

Autophagy is a double-edged sword in cancer, and numerous aspects should be taken into account before deciding on the most effective strategy to target the process. The fact that several clinical studies are now ongoing does not mean that the patient group that may benefit from autophagy-targeting medicines has been identified. Autophagy inhibitors that are more potent and specialized, as well as autophagy indicators, are also desperately required. The fact that these inhibitors only work against tumors that rely on autophagy for survival (RAS mutants) makes it difficult to distinguish them from tumors that continue to develop even when autophagy is absent. Furthermore, mutations such as BRAF have been shown to make tumors more susceptible to autophagy suppression, suggesting that targeting such tumours may be a viable strategy for overcoming their chemotherapy resistance. In the meantime, we are unable to identify if autophagy regulation works in vivo or whether it selectively targets a disease while inflicting injury to other healthy organs and tissues. A cell-type-specific impact appears to be observed with such therapy. As a result, it is just as important to consider the differences between tumors that originate in different organs as it is to consider the signaling pathways that are similar across them. For a therapy or cure to be effective, the proposed intervention must be tailored to the specific needs of each patient.Over the last several years, a growing amount of data has implicated autophagy in a variety of disorders, including cancer. In normal cells, this catabolic process is also required for cell survival and homeostasis. Despite the fact that medications targeting intermediates in the autophagy signaling pathway are being created and evaluated at both the preclinical and clinical levels, given the complicated function of autophagy in cancer, we still have a long way to go in terms of establishing an effective therapeutic approach. This article discusses current tactics for exploiting cancer cells' autophagy dependency, as well as obstacles in the area. We believe that the unanswered concerns raised in this work will stimulate researchers to investigate previously unknown connections between autophagy and other signaling pathways, which might lead to the development of novel, highly specialized autophagy therapies.

scholarly journals Dual Inactivation of RB and p53 Pathways in RAS-Induced Melanomas

2001 ◽  
Vol 21 (6) ◽  
pp. 2144-2153 ◽  
Author(s):  
Nabeel Bardeesy ◽  
Boris C. Bastian ◽  
Aram Hezel ◽  
Dan Pinkel ◽  
Ronald A. DePinho ◽  
...  
Keyword(s):  
Tumor Cells ◽  
P53 Mutation ◽  
Comparative Genomic ◽  
Cell Type ◽  
Specific Expression ◽  
Rb Pathway ◽  
High Incidence ◽  
A Cell ◽  
Cell Type Specific

ABSTRACT The frequent loss of both INK4a and ARF in melanoma raises the question of which INK4a-ARF gene product functions to suppress melanoma genesis in vivo. Moreover, the high incidence of INK4a-ARF inactivation in transformed melanocytes, along with the lack of p53 mutation, implies a cell type-specific role for INK4a-ARF that may not be complemented by other lesions of the RB and p53 pathways. A mouse model of cutaneous melanoma has been generated previously through the combined effects of INK4a Δ2/3 deficiency (null for INK4a and ARF) and melanocyte-specific expression of activated RAS (tyrosinase-driven H-RASV12G, Tyr-RAS). In this study, we made use of this Tyr-RAS allele to determine whether activated RAS can cooperate withp53 loss in melanoma genesis, whether such melanomas are biologically comparable to those arising inINK4a Δ2/3−/− mice, and whether tumor-associated mutations emerge in the p16INK4a-RB pathway in such melanomas. Here, we report that p53inactivation can cooperate with activated RAS to promote the development of cutaneous melanomas that are clinically indistinguishable from those arisen on theINK4a Δ2/3 null background. Genomewide analysis of RAS-induced p53 mutant melanomas by comparative genomic hybridization and candidate gene surveys revealed alterations of key components governing RB-regulated G1/S transition, including c-Myc, cyclin D1, cdc25a, and p21CIP1. Consistent with the profile of c-Myc dysregulation, the reintroduction of p16INK4a profoundly reduced the growth of Tyr-RASINK4a Δ2/3−/− tumor cells but had no effect on tumor cells derived from Tyr-RAS p53 −/−melanomas. Together, these data validate a role for p53inactivation in melanomagenesis and suggest that both the RB and p53 pathways function to suppress melanocyte transformation in vivo in the mouse.

Na+,K+-ATPase as a Target for Treatment of Tissue Fibrosis

2019 ◽  
Vol 26 (3) ◽  
pp. 564-575 ◽  
Author(s):  
Sergei N. Orlov ◽  
Jennifer La ◽  
Larisa V. Smolyaninova ◽  
Nickolai O. Dulin
Keyword(s):  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Lung Fibroblasts ◽  
In Vivo Studies ◽  
Myofibroblast Differentiation ◽  
Cell Type ◽  
Tissue Fibrosis ◽  
Cell Type Specific ◽  
Cox 2

Myofibroblast activation is a critical process in the pathogenesis of tissue fibrosis accounting for 45% of all deaths. No effective therapies are available for the treatment of fibrotic diseases. We focus our mini-review on recent data showing that cardiotonic steroids (CTS) that are known as potent inhibitors of Na+,K+-ATPase affect myofibroblast differentiation in a cell type-specific manner. In cultured human lung fibroblasts (HLF), epithelial cells, and cancer-associated fibroblasts, CTS blocked myofibroblast differentiation triggered by profibrotic cytokine TGF-β. In contrast, in the absence of TGF-β, CTS augmented myofibroblast differentiation of cultured cardiac fibroblasts. The cell type-specific action of CTS in myofibroblast differentiation is consistent with data obtained in in vivo studies. Thus, infusion of ouabain via osmotic mini-pumps attenuated the development of lung fibrosis in bleomycintreated mice, whereas marinobufagenin stimulated renal and cardiac fibrosis in rats with experimental renal injury. In TGF-β-treated HLF, suppression of myofibroblast differentiation by ouabain is mediated by elevation of the [Na+]i/[K+]i ratio and is accompanied by upregulation of cyclooxygenase COX-2 and downregulation of TGF-β receptor TGFBR2. Augmented expression of COX-2 is abolished by inhibition of Na+/Ca2+ exchanger, suggesting a key role of [Ca2+]i-mediated signaling. What is the relative impact in tissue fibrosis of [Na+]i,[K+]iindependent signaling documented in several types of CTS-treated cells? Do the different conformational transitions of Na+,K+-ATPase α1 subunit in the presence of ouabain and marinobufagenin contribute to their distinct involvement in myofibroblast differentiation? Additional experiments should be done to answer these questions and to develop novel pharmacological approaches for the treatment of fibrosis-related disorders.

Glial fibrillary acidic protein - a cell type specific marker for Ito cells in vivo and in vitro

1996 ◽  
Vol 24 (6) ◽  
pp. 719-730 ◽  
Author(s):  
Katrin Neubauer ◽  
Thomas Knittel ◽  
Sabine Aurisch ◽  
Peter Fellmer ◽  
Giuliano Ramadori
Keyword(s):  
Glial Fibrillary Acidic Protein ◽  
Protein A ◽  
Acidic Protein ◽  
Specific Marker ◽  
Cell Type ◽  
Ito Cells ◽  
A Cell ◽  
Cell Type Specific

Phosphatase Wip1 negatively regulates neutrophil development through p38 MAPK-STAT1

Blood ◽  
2013 ◽  
Vol 121 (3) ◽  
pp. 519-529 ◽  
Author(s):  
Guangwei Liu ◽  
Xuelian Hu ◽  
Bo Sun ◽  
Tao Yang ◽  
Jianfeng Shi ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Molecular Mechanisms ◽  
Negative Regulator ◽  
Cell Type ◽  
A Cell ◽  
Cell Type Specific ◽  
Neutrophil Differentiation ◽  
Deficient Mice

Abstract Neutrophils are critically involved in host defense and tissue damage. Intrinsic molecular mechanisms controlling neutrophil differentiation and activities are poorly defined. Herein we found that p53-induced phosphatase 1(Wip1) is preferentially expressed in neutrophils among immune cells. The Wip1 expression is gradually up-regulated during the differentiation of myeloid precursors into mature neutrophils. Wip1-deficient mice and chimera mice with Wip1−/− hematopoietic cells had an expanded pool of neutrophils with hypermature phenotypes in the periphery. The in vivo and in vitro studies showed that Wip1 deficiency mainly impaired the developing process of myeloid progenitors to neutrophils in an intrinsic manner. Mechanism studies showed that the enhanced development and maturation of neutrophils caused by Wip1 deficiency were mediated by p38 MAPK-STAT1 but not p53-dependent pathways. Thus, our findings identify a previously unrecognized p53-independent function of Wip1 as a cell type-specific negative regulator of neutrophil generation and homeostasis through limiting the p38 MAPK-STAT1 pathway.

scholarly journals Prdm16-mediated H3K9 methylation controls fibro-adipogenic progenitors identity during skeletal muscle repair

2021 ◽  
Vol 7 (23) ◽  
pp. eabd9371
Author(s):  
Beatrice Biferali ◽  
Valeria Bianconi ◽  
Daniel Fernandez Perez ◽  
Sophie Pöhle Kronawitter ◽  
Fabrizia Marullo ◽  
...  
Keyword(s):  
Envelope Protein ◽  
Nuclear Periphery ◽  
Nuclear Lamina ◽  
H3k9 Methylation ◽  
Cell Type ◽  
Specific Manner ◽  
A Cell ◽  
Cell Type Specific ◽  
Genomic Regions

H3K9 methylation maintains cell identity orchestrating stable silencing and anchoring of alternate fate genes within the heterochromatic compartment underneath the nuclear lamina (NL). However, how cell type–specific genomic regions are specifically targeted to the NL is still elusive. Using fibro-adipogenic progenitors (FAPs) as a model, we identified Prdm16 as a nuclear envelope protein that anchors H3K9-methylated chromatin in a cell-specific manner. We show that Prdm16 mediates FAP developmental capacities by orchestrating lamina-associated domain organization and heterochromatin sequestration at the nuclear periphery. We found that Prdm16 localizes at the NL where it cooperates with the H3K9 methyltransferases G9a/GLP to mediate tethering and silencing of myogenic genes, thus repressing an alternative myogenic fate in FAPs. Genetic and pharmacological disruption of this repressive pathway confers to FAP myogenic competence, preventing fibro-adipogenic degeneration of dystrophic muscles. In summary, we reveal a druggable mechanism of heterochromatin perinuclear sequestration exploitable to reprogram FAPs in vivo.

scholarly journals Genistein Enhances or Reduces Glycosaminoglycan Quantity in a Cell Type-Specific Manner

2018 ◽  
Vol 47 (4) ◽  
pp. 1667-1681
Author(s):  
Ying Lan ◽  
Xiulian Li ◽  
Xuebo Liu ◽  
Cui Hao ◽  
Ni Song ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Isotope Labeling ◽  
Dependent Manner ◽  
Cell Type ◽  
Beneficial Effects ◽  
Genistein Treatment ◽  
Specific Manner ◽  
A Cell ◽  
Cell Type Specific ◽  
Hct116 Cells

Background/Aims: Genistein is a natural isoflavone enriched in soybeans. It has beneficial effects for patients with mucopolysaccharidose type III through inhibiting glycosaminoglycan biosynthesis. However, other studies indicate that genistein does not always inhibit glycosaminoglycan biosynthesis. Methods: To understand the underlying molecular mechanisms, CHOK1, CHO3.1, CHO3.3, and HCT116 cells were treated with genistein and the monosaccharide compositions and quantity of all glycans from the cell lysate were measured after thorough acid hydrolysis followed by HPLC analysis. In addition, the glycosaminoglycan disaccharide compositions were obtained by stable isotope labeling coupled with LC/MS analysis. Results: Genistein treatment reduced the amount of glycans but increased the amount of glycosaminoglycans in HCT116 cells. In contrast, genistein treatment reduced both glycan and glycosaminoglycan quantities in CHOK1, CHO3.1, and CHO3.3 cells in addition to differential changes in glycosaminoglycan disaccharide compositions. Conclusion: Genistein treatment reduced overall glycan quantity but glycosaminoglycan quantities were either increased or decreased in a cell type-dependent manner.

scholarly journals Heterogeneity of Transcription Factor binding specificity models within and across cell lines

2015 ◽  
Author(s):  
Mahfuza Sharmin ◽  
Hector Corrada Bravo ◽  
Sridhar S. Hannenhalli
Keyword(s):  
Expression Patterns ◽  
Specific Interaction ◽  
Cell Types ◽  
Cell Type ◽  
Binding Interaction ◽  
Interaction Partners ◽  
A Cell ◽  
Cell Type Specific ◽  
Different Cell Types

Complex gene expression patterns are mediated by binding of transcription factors (TF) to specific genomic loci. The in vivo occupancy of a TF is, in large part, determined by the TFs DNA binding interaction partners, motivating genomic context based models of TF occupancy. However, the approaches thus far have assumed a uniform binding model to explain genome wide bound sites for a TF in a cell-type and as such heterogeneity of TF occupancy models, and the extent to which binding rules underlying a TFs occupancy are shared across cell types, has not been investigated. Here, we develop an ensemble based approach (TRISECT) to identify heterogeneous binding rules of cell-type specific TF occupancy and analyze the inter-cell-type sharing of such rules. Comprehensive analysis of 23 TFs, each with ChIP-Seq data in 4-12 cell-types, shows that by explicitly capturing the heterogeneity of binding rules, TRISECT accurately identifies in vivo TF occupancy (93%) substantially improving upon previous methods. Importantly, many of the binding rules derived from individual cell-types are shared across cell-types and reveal distinct yet functionally coherent putative target genes in different cell-types. Closer inspection of the predicted cell-type-specific interaction partners provides insights into context-specific functional landscape of a TF. Together, our novel ensemble-based approach reveals, for the first time, a widespread heterogeneity of binding rules, comprising interaction partners within a cell-type, many of which nevertheless transcend cell-types. Notably, the putative targets of shared binding rules in different cell-types, while distinct, exhibit significant functional coherence.

scholarly journals The glycosaminoglycan-binding domain of PRELP acts as a cell type–specific NF-κB inhibitor that impairs osteoclastogenesis

2009 ◽  
Vol 187 (5) ◽  
pp. 669-683 ◽  
Author(s):  
Nadia Rucci ◽  
Anna Rufo ◽  
Marina Alamanou ◽  
Mattia Capulli ◽  
Andrea Del Fattore ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Basement Membranes ◽  
Binding Domain ◽  
Mitogen Activated Protein Kinase ◽  
Specific Gene ◽  
Cell Type ◽  
Ovariectomized Mice ◽  
A Cell ◽  
Cell Type Specific

Proline/arginine-rich end leucine-rich repeat protein (PRELP) is a glycosaminoglycan (GAG)- and collagen-binding anchor protein highly expressed in cartilage, basement membranes, and developing bone. We observed that PRELP inhibited in vitro and in vivo mouse osteoclastogenesis through its GAG-binding domain (hbdPRELP), involving (a) cell internalization through a chondroitin sulfate– and annexin II–dependent mechanism, (b) nuclear translocation, (c) interaction with p65 nuclear factor κB (NF-κB) and inhibition of its DNA binding, and (d) impairment of NF-κB transcriptional activity and reduction of osteoclast-specific gene expression. hbdPRELP does not disrupt the mitogen-activated protein kinase signaling nor does it impair cell survival. hbdPRELP activity is cell type specific, given that it is internalized by the RAW264.7 osteoclast-like cell line but fails to affect calvarial osteoblasts, bone marrow macrophages, and epithelial cell lines. In vivo, hbdPRELP reduces osteoclast number and activity in ovariectomized mice, underlying its physiological and/or pathological importance in skeletal remodeling.

IFIH1-deficiency results in a cell-type specific alteration of autophagic activity in response to S. typhimurium

2017 ◽  
Vol 55 (05) ◽  
pp. e28-e56
Author(s):  
S Macheiner ◽  
R Gerner ◽  
A Pfister ◽  
A Moschen ◽  
H Tilg
Keyword(s):  
Cell Type ◽  
A Cell ◽  
Cell Type Specific ◽  
Autophagic Activity ◽  
Specific Alteration
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