scholarly journals Fetal hyperinsulinemia increases farnesylation of p21 Ras in fetal tissues

2001 ◽  
Vol 281 (2) ◽  
pp. E217-E223 ◽  
Author(s):  
Elizabeth Stephens ◽  
Patti J. Thureen ◽  
Marc L. Goalstone ◽  
Marianne S. Anderson ◽  
J. Wayne Leitner ◽  
...  
Keyword(s):  
Growth Factors ◽  
Molecular Mechanisms ◽  
Fetal Liver ◽  
White Blood Cells ◽  
Causative Factor ◽  
Ras Proteins ◽  
Direct Infusion ◽  
Fetal Tissues ◽  
P21 Ras

Even though the role of fetal hyperinsulinemia in the pathogenesis of fetal macrosomia in patients with overt diabetes and gestational diabetes mellitus seems plausible, the molecular mechanisms of action of hyperinsulinemia remain largely enigmatic. Recent indications that hyperinsulinemia “primes” various tissues to the mitogenic influence of growth factors by increasing the pool of prenylated Ras proteins prompted us to investigate the effect of fetal hyperinsulinemia on the activitiy of farnesyltransferase (FTase) and the amounts of farnesylated p21 Ras in fetal tissues in the ovine experimental model. Induction of fetal hyperinsulinemia by direct infusion of insulin into the fetus and by either fetal or maternal infusions of glucose resulted in significant increases in the activity of FTase and the amounts of farnesylated p21 Ras in fetal liver, skeletal muscle, fat, and white blood cells. An additional infusion of somatostatin into hyperglycemic fetuses blocked fetal hyperinsulinemia and completely prevented these increases, specifying insulin as the causative factor. We conclude that the ability of fetal hyperinsulinemia to increase the size of the pool of farnesylated p21 Ras may prime fetal tissues to the action of other growth factors and thereby constitute one mechanism by which fetal hyperinsulinemia could induce macrosomia in diabetic pregnancies.

scholarly journals Bone remodeling stages under physiological conditions and glucocorticoid in excess: Focus on cellular and molecular mechanisms

2021 ◽  
Vol 12 (2) ◽  
pp. 212-227
Author(s):  
V. V. Povoroznyuk ◽  
N. V. Dedukh ◽  
M. A. Bystrytska ◽  
V. S. Shapovalov
Keyword(s):  
Growth Factors ◽  
Bone Resorption ◽  
Signaling Pathways ◽  
Bone Remodeling ◽  
Molecular Mechanisms ◽  
Signaling Molecules ◽  
Physiological Conditions ◽  
Bone Cell Differentiation ◽  
Repressive Effect

This review provides a rationale for the cellular and molecular mechanisms of bone remodeling stages under physiological conditions and glucocorticoids (GCs) in excess. Remodeling is a synchronous process involving bone resorption and formation, proceeding through stages of: (1) resting bone, (2) activation, (3) bone resorption, (4) reversal, (5) formation, (6) termination. Bone remodeling is strictly controlled by local and systemic regulatory signaling molecules. This review presents current data on the interaction of osteoclasts, osteoblasts and osteocytes in bone remodeling and defines the role of osteoprogenitor cells located above the resorption area in the form of canopies and populating resorption cavities. The signaling pathways of proliferation, differentiation, viability, and cell death during remodeling are presented. The study of signaling pathways is critical to understanding bone remodeling under normal and pathological conditions. The main signaling pathways that control bone resorption and formation are RANK / RANKL / OPG; M-CSF – c-FMS; canonical and non-canonical signaling pathways Wnt; Notch; MARK; TGFβ / SMAD; ephrinB1/ephrinB2 – EphB4, TNFα – TNFβ, and Bim – Bax/Bak. Cytokines, growth factors, prostaglandins, parathyroid hormone, vitamin D, calcitonin, and estrogens also act as regulators of bone remodeling. The role of non-encoding microRNAs and long RNAs in the process of bone cell differentiation has been established. MicroRNAs affect many target genes, have both a repressive effect on bone formation and activate osteoblast differentiation in different ways. Excess of glucocorticoids negatively affects all stages of bone remodeling, disrupts molecular signaling, induces apoptosis of osteocytes and osteoblasts in different ways, and increases the life cycle of osteoclasts. Glucocorticoids disrupt the reversal stage, which is critical for the subsequent stages of remodeling. Negative effects of GCs on signaling molecules of the canonical Wingless (WNT)/β-catenin pathway and other signaling pathways impair osteoblastogenesis. Under the influence of excess glucocorticoids biosynthesis of biologically active growth factors is reduced, which leads to a decrease in the expression by osteoblasts of molecules that form the osteoid. Glucocorticoids stimulate the expression of mineralization inhibitor proteins, osteoid mineralization is delayed, which is accompanied by increased local matrix demineralization. Although many signaling pathways involved in bone resorption and formation have been discovered and described, the temporal and spatial mechanisms of their sequential turn-on and turn-off in cell proliferation and differentiation require additional research.

Essential Role of Kindlin 3 in Zebrafish Thrombopoiesis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1166-1166
Author(s):  
James J. Mann ◽  
Nathaniel B. Langer ◽  
Andrew Woo ◽  
Tyler B. Moran ◽  
Yocheved Schindler ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Zinc Finger ◽  
Essential Role ◽  
Molecular Mechanisms ◽  
Fetal Liver ◽  
Affinity Purification ◽  
Transgenic Zebrafish ◽  
Zinc Finger Transcription Factor ◽  
Stage Of Development

Abstract The zinc finger transcription factor GATA-1 is required for proliferative inhibition and terminal maturation of megakaryocytes, and is mutated in Down Syndrome Transient Myeloproliferative Disorder (TMD) and Acute Megakaryoblastic Leukemia (DS-AMKL). Yet the molecular mechanisms that regulate GATA-1 activity in megakaryopoiesis remain incompletely understood. Many transcription factors, in addition to binding DNA, make important protein-protein interactions that modulate their activity. In order to further understand GATA-1’s function, and possibly identify new factors involved in megakaryopoiesis, we purified GATA-1 containing multiprotein complexes from the murine L8057 megakaryocytic cell line. We generated stable L8057 cell lines expressing metabolically biotinylated and FLAG epitope tagged GATA-1, and then performed a tandem anti-FLAG immunoaffinity and streptavidin affinity purification. Using mass spectrometry (LC/MS/MS), we identified the known GATA-1 associated proteins Friend of GATA-1 (FOG-1), SCL, Ldb1, Runx-1/Cbf-β. SP1 and all components of the NuRD complex (which binds FOG-1) as co-purifying proteins. In addition, we reproducibly obtained several novel proteins. We previously reported the identification of the kruppel-type zinc finger transcription factor zfp148 (also called ZBP-89), and showed that it plays an essential role in megakaryopoiesis and definitive erythropoiesis. Here we report the identification of Kindlin 3 (also called URP2 for UNC-112 related protein 2), a member of a family of PH and FERM domain containing proteins that are thought to play a role in integrin-mediated processes. Expression of Kindlin 3 is restricted to hematopoietic cells, principally megakaryocytes and lymphocytes. It is first expressed at ~E9.5 during murine embryogenesis, and is abundant in fetal liver megakaryocytes by day E14.5. In order to begin to assess the role of Kindlin 3 in megakaryopoiesis in vivo, we performed morpholino-mediated knockdown of Kindlin 3 expression in CD41-GFP transgenic zebrafish embryos. In contrast to control embryos, embryos injected with Kindlin 3 specific morpholinos exhibited nearly complete loss of GFP+ thrombocytes (equivalent to mammalian megakaryocyte/platelets). Erythroid development (equivalent to mammalian primitive erythropoiesis at this stage of development) was not significantly affected, similar to embryos injected with zfp148-specific morpholinos. Given the role of integrin outside-to-inside signaling in megakaryopoiesis, we propose that Kindlin 3 may play a role linking extracellular signals to megakaryocyte maturation and growth control via GATA-1 transcription complexes. Further analysis in murine systems is underway to test this hypothesis.

Unactivated platelet leukocyte autoplasma in the treatment of non scarring alopecia

2016 ◽  
Vol 19 (6) ◽  
pp. 369-377
Author(s):  
G. A Ragimov ◽  
O. Yu Olisova ◽  
Kseniya G. Egorova
Keyword(s):  
Growth Factors ◽  
Clinical Cure ◽  
Clinical Observation ◽  
Platelet Rich Plasma ◽  
White Blood Cells ◽  
Treatment Method ◽  
Hair Follicles ◽  
Scarring Alopecia ◽  
Platelet Concentration

The literature review of the cellular functioning mechanisms of the hair follicles, the role of stem cells in the life cycle of the hair, the major effects of growth factors are presented. Authors, patented treatment method of non scarring alopecia is described. The technology ofpreparation and method of use of unactivated platelet leukocyte autoplasma in various forms of alopecia are described. Own clinical observation of 60 patients with non scarring alopecia and results of their unactivated platelet leukocyte autoplasma are presented. 80% of patients had a clinical cure. Investigations of platelet concentration, white blood cells and growth factors in platelet-rich plasma and platelet leukocyte unactivated autoplasma were performed. The results are shown in the article.

scholarly journals Role of White Blood Cells in Blood- and Bone Marrow-Based Autologous Therapies

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
William King ◽  
Krista Toler ◽  
Jennifer Woodell-May
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Growth Factors ◽  
Blood Cells ◽  
Platelet Rich Plasma ◽  
White Blood Cells ◽  
Complex Mixture ◽  
Negative Results

There has been significant debate over the role of white blood cells (WBCs) in autologous therapies, with several groups suggesting that WBCs are purely inflammatory. Misconceptions in the practice of biologic orthopedics result in the simplified principle that platelets deliver growth factors, WBCs cause inflammation, and the singular value of bone marrow is the stem cells. The aim of this review is to address these common misconceptions which will enable better development of future orthopedic medical devices. WBC behavior is adaptive in nature and, depending on their environment, WBCs can hinder or induce healing. Successful tissue repair occurs when platelets arrive at a wound site, degranulate, and release growth factors and cytokines which, in turn, recruit WBCs to the damaged tissue. Therefore, a key role of even pure platelet-rich plasma is to recruit WBCs to a wound. Bone marrow contains a complex mixture of vascular cells, white blood cells present at much greater concentrations than in blood, and a small number of progenitor cells and stem cells. The negative results observed for WBC-containing autologous therapies in vitro have not translated to human clinical studies. With an enhanced understanding of the complex WBC biology, the next generation of biologics will be more specific, likely resulting in improved effectiveness.

Hematologic effects of inactivating the Ras processing enzymeRce1

Blood ◽  
2003 ◽  
Vol 101 (6) ◽  
pp. 2250-2252 ◽  
Author(s):  
Abigail L. Aiyagari ◽  
Brigit R. Taylor ◽  
Vikas Aurora ◽  
Stephen G. Young ◽  
Kevin M. Shannon
Keyword(s):  
Bone Marrow Cells ◽  
Fetal Liver ◽  
Ras Proteins ◽  
Extracellular Signal ◽  
Macrophage Colony Stimulating Factor ◽  
Carboxyl Terminal ◽  
Macrophage Colony ◽  
Prenylated Proteins

Posttranslational processing of Ras proteins has attracted considerable interest as a potential target for anticancer drug discovery. Rce1 encodes an endoprotease that facilitates membrane targeting of Ras and other prenylated proteins by releasing the carboxyl-terminal 3 amino acids (ie, the -AAX of the CAAX motif). Homozygous Rce1 mutant embryos(Rce1−/−) die late in gestation. To characterize the role of Rce1 in hematopoiesis, we performed adoptive transfers and investigated cells from the recipients. Rce1−/− fetal liver cells rescued lethally irradiated recipients and manifested normal long-term repopulating potential in competitive repopulation assays. The recipients of Rce1−/− cells developed modest elevations in mature myeloid cells (neutrophils + monocytes), but remained well. Bone marrow cells from mice that received transplants of Rce1−/− activated extracellular signal-related kinase (ERK) normally in response to granulocyte-macrophage colony-stimulating factor. These data suggest that pharmacologic inhibitors of Rce1 will have minimal effects on normal hematopoietic cells.

scholarly journals The role of the immune system in idiopathic nephrotic syndrome

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Agnes Hackl ◽  
Seif El Din Abo Zed ◽  
Paul Diefenhardt ◽  
Julia Binz-Lotter ◽  
Rasmus Ehren ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Immune System ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Idiopathic Nephrotic Syndrome ◽  
Cell Subset ◽  
Causative Factor ◽  
Direct Role ◽  
Filtration Barrier

AbstractIdiopathic nephrotic syndrome (INS) in children is characterized by massive proteinuria and hypoalbuminemia and usually responds well to steroids. However, relapses are frequent, which can require multi-drug therapy with deleterious long-term side effects. In the last decades, different hypotheses on molecular mechanisms underlying INS have been proposed and several lines of evidences strongly indicate a crucial role of the immune system in the pathogenesis of non-genetic INS. INS is traditionally considered a T-cell-mediated disorder triggered by a circulating factor, which causes the impairment of the glomerular filtration barrier and subsequent proteinuria. Additionally, the imbalance between Th17/Tregs as well as Th2/Th1 has been implicated in the pathomechanism of INS. Interestingly, B-cells have gained attention, since rituximab, an anti-CD20 antibody demonstrated a good therapeutic response in the treatment of INS. Finally, recent findings indicate that even podocytes can act as antigen-presenting cells under inflammatory stimuli and play a direct role in activating cellular pathways that cause proteinuria. Even though our knowledge on the underlying mechanisms of INS is still incomplete, it became clear that instead of a traditionally implicated cell subset or one particular molecule as a causative factor for INS, a multi-step control system including soluble factors, immune cells, and podocytes is necessary to prevent the occurrence of INS. This present review aims to provide an overview of the current knowledge on this topic, since advances in our understanding of the immunopathogenesis of INS may help drive new tailored therapeutic approaches forward.

The role of Raf kinases in malignant transformation

2002 ◽  
Vol 4 (8) ◽  
pp. 1-18 ◽  
Author(s):  
Walter Kolch ◽  
Ashwin Kotwaliwale ◽  
Keith Vass ◽  
Petra Janosch
Keyword(s):  
Molecular Mechanisms ◽  
Mitogen Activated Protein Kinase ◽  
Ras Proteins ◽  
Surface Receptors ◽  
Extracellular Signal Regulated Kinase ◽  
Raf Kinase ◽  
Growth Inhibitory ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

The Raf kinases are proto-oncogenes that work at the entry point of the mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathway, a signalling module that connects cell-surface receptors and Ras proteins to nuclear transcription factors. The pathway impinges on all the functional hallmarks of cancer cells: immortalisation, growth-factor-independent proliferation, insensitivity to growth-inhibitory signals, ability to invade and metastasise, ability to attract blood vessels, and evasion of apoptosis. Indeed, the pathway is hyperactivated in 30% of all human tumours including prevalent cancers of the colon and lung. The molecular mechanisms underlying the role of Raf kinase in tumourigenesis and the opportunities for therapeutic intervention are reviewed in this article.

scholarly journals Insulin induction of Xenopus laevis oocyte maturation is inhibited by monoclonal antibody against p21 ras proteins.

1987 ◽  
Vol 7 (3) ◽  
pp. 1285-1288 ◽  
Author(s):  
A K Deshpande ◽  
H F Kung
Keyword(s):  
Monoclonal Antibody ◽  
Xenopus Laevis ◽  
Oocyte Maturation ◽  
Neutralizing Antibody ◽  
Xenopus Laevis Oocytes ◽  
Xenopus Laevis Oocyte ◽  
Ras Proteins ◽  
Ras Protein ◽  
P21 Ras

Microinjection of transforming p21 ras protein induces maturation of Xenopus laevis oocytes, and the induction is blocked by coinjection of monoclonal antibody (Y13-259) against p21 ras proteins. Similar to other inducing agents, the effect of p21 ras protein is mediated via the appearance of maturation or meiosis-promoting factor activity. In addition, the neutralizing antibody markedly reduces oocyte maturation after insulin induction, whereas it fails to inhibit progesterone induction. Our results suggest that insulin induces maturation of oocytes via a different pathway than that of steroidal agents. The induction by insulin is ras dependent, and the action of ras may be directed at the steps before meiosis-promoting factor autocatalytic activation. These results suggest a role of p21 ras protein in the events associated with amphibian oocyte maturation.

scholarly journals Histone acetyltransferase and Polo-like kinase 3 inhibitors prevent rat galactose-induced cataract

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Fumito Kanada ◽  
Yoshihiro Takamura ◽  
Seiji Miyake ◽  
Kazuma Kamata ◽  
Mayumi Inami ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Histone Acetyltransferase ◽  
Ex Vivo ◽  
Causative Factor ◽  
Mrna Levels ◽  
Cataract Formation ◽  
Diabetic Cataract ◽  
Novel Approach ◽  
Hat Inhibitor

AbstractDiabetic cataracts can occur at an early age, causing visual impairment or blindness. The detailed molecular mechanisms of diabetic cataract formation remain incompletely understood, and there is no well-documented prophylactic agent. Galactose-fed rats and ex vivo treatment of lenses with galactose are used as models of diabetic cataract. To assess the role of histone acetyltransferases, we conducted cataract prevention screening with known histone acetyltransferase (HAT) inhibitors. Ex vivo treatment with a HAT inhibitor strongly inhibited the formation of lens turbidity in high-galactose conditions, while addition of a histone deacetylase (HDAC) inhibitor aggravated turbidity. We conducted a microarray to identify genes differentially regulated by HATs and HDACs, leading to discovery of a novel cataract causative factor, Plk3. Plk3 mRNA levels correlated with the degree of turbidity, and Plk3 inhibition alleviated galactose-induced cataract formation. These findings indicate that epigenetically controlled Plk3 influences cataract formation. Our results demonstrate a novel approach for prevention of diabetic cataract using HAT and Plk3 inhibitors.

Insulin induction of Xenopus laevis oocyte maturation is inhibited by monoclonal antibody against p21 ras proteins

1987 ◽  
Vol 7 (3) ◽  
pp. 1285-1288
Author(s):  
A K Deshpande ◽  
H F Kung
Keyword(s):  
Monoclonal Antibody ◽  
Xenopus Laevis ◽  
Oocyte Maturation ◽  
Neutralizing Antibody ◽  
Xenopus Laevis Oocytes ◽  
Xenopus Laevis Oocyte ◽  
Ras Proteins ◽  
Ras Protein ◽  
P21 Ras

Microinjection of transforming p21 ras protein induces maturation of Xenopus laevis oocytes, and the induction is blocked by coinjection of monoclonal antibody (Y13-259) against p21 ras proteins. Similar to other inducing agents, the effect of p21 ras protein is mediated via the appearance of maturation or meiosis-promoting factor activity. In addition, the neutralizing antibody markedly reduces oocyte maturation after insulin induction, whereas it fails to inhibit progesterone induction. Our results suggest that insulin induces maturation of oocytes via a different pathway than that of steroidal agents. The induction by insulin is ras dependent, and the action of ras may be directed at the steps before meiosis-promoting factor autocatalytic activation. These results suggest a role of p21 ras protein in the events associated with amphibian oocyte maturation.

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