Modulation of bone marrow and peripheral blood cytokine levels by age and clonal hematopoiesis in healthy individuals.

Aging is associated with bone marrow (BM) inflammaging and, in some individuals, with the onset of clonal hematopoiesis (CH) of indeterminate potential. In this study conducted on 94 strictly healthy volunteers (18 to 80 yo), we measured BM and peripheral blood (PB) plasma levels of 49 hematopoietic and inflammatory cytokines. With aging, 7 cytokines increased in BM (FLT3L, CXCL9, HGF, FGF-2, CCL27, IL-16, IL-18) and 8 decreased (G-CSF, TNF, IL-2, IL-15, IL-17A, CCL7, IL-4, IL-10).

A New in Silico Antibody Similarity Measure Both Identifies Large Sets of Epitope Binders with Distinct CDRs and Accurately Predicts Off-Target Reactivity.

Developing a therapeutic antibody is a long, tedious, and expensive process. Many obstacles need to be overcome, such as biophysical properties (issues of solubility, stability, weak production yields, etc.), as well as cross-reactivity and subsequent toxicity, which are major issues.

Aberrant DNA methylation impacts HOX genes expression in bone marrow mesenchymal stromal cells of myelodysplastic syndromes and de novo acute myeloid leukemia.

DNA methylation, a major biological process regulating the transcription, contributes to the pathophysiology of hematologic malignancies, and hypomethylating agents are commonly used to treat myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). In these diseases, bone marrow mesenchymal stromal cells (MSCs) play a key supportive role through the production of various signals and interactions. The DNA methylation status of MSCs, likely to reflect their functionality, might be relevant to understand their contribution to the pathophysiology of these diseases.

Pharmacological Characterization of Low Molecular Weight Biased Agonists at the Follicle Stimulating Hormone Receptor.

Follicle-stimulating hormone receptor (FSHR) plays a key role in reproduction through the activation of multiple signaling pathways. Low molecular weight (LMW) ligands composed of biased agonist properties are highly valuable tools to decipher complex signaling mechanisms as they allow selective activation of discrete signaling cascades. However, available LMW FSHR ligands have not been fully characterized yet.

Involvement of GPx-3 in the Reciprocal Control of Redox Metabolism in the Leukemic Niche.

The bone marrow (BM) microenvironment plays a crucial role in the development and progression of leukemia (AML). Intracellular reactive oxygen species (ROS) are involved in the regulation of the biology of leukemia-initiating cells, where the antioxidant enzyme GPx-3 could be involved as a determinant of cellular self-renewal. Little is known however about the role of the microenvironment in the control of the oxidative metabolism of AML cells.

High prevalence of clonal hematopoiesis in the blood and bone marrow of healthy volunteers.

Clonal hematopoiesis (CH) of indeterminate potential has been described in blood samples from large series of patients. Its prevalence and consequences are still not well understood because sequencing methods vary and because most studies were performed in cohorts comprising individuals with nonhematologic diseases. Here, we investigated the frequency of CH in 82 paired bone marrow and blood samples from carefully selected healthy adult volunteers.

Bone marrow oxidative stress and specific antioxidant signatures in myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders with an inherent tendency for transformation in secondary acute myeloid leukemia. This study focused on the redox metabolism of bone marrow (BM) cells from 97 patients compared with 25 healthy controls. The level of reactive oxygen species (ROS) was quantified by flow cytometry in BM cell subsets as well as the expression level of 28 transcripts encoding for major enzymes involved in the antioxidant cellular response.

MAbTope: A Method for Improved Epitope Mapping.

Abs are very efficient drugs, ∼70 of them are already approved for medical use, over 500 are in clinical development, and many more are in preclinical development. One important step in the characterization and protection of a therapeutic Ab is the determination of its cognate epitope. The gold standard is the three-dimensional structure of the Ab/Ag complex by crystallography or nuclear magnetic resonance spectroscopy.

n-3 Polyunsaturated fatty acids induce acute myeloid leukemia cell death associated with mitochondrial glycolytic switch and Nrf2 pathway activation.

Acute Myeloid Leukemia (AML) remains a therapeutic challenge and improvements in chemotherapy are needed. n-3 polyunsaturated fatty acids (PUFAs), present in fish oil (FO) at high concentrations, have antitumoral properties in various cancer models. We investigated the effects of two n-3 PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), in AML cell lines and primary AML blasts.

Human Luteinizing Hormone and Chorionic Gonadotropin Display Biased Agonism at the LH and LH/CG Receptors.

Human luteinizing hormone (LH) and chorionic gonadotropin (hCG) have been considered biologically equivalent because of their structural similarities and their binding to the same receptor; the LH/CGR. However, accumulating evidence suggest that LH/CGR differentially responds to the two hormones triggering differential intracellular signaling and steroidogenesis. The mechanistic basis of such differential responses remains mostly unknown.

Phosphorylation of β-arrestin2 at Thr by MEK underlies β-arrestin-dependent activation of Erk1/2 by GPCRs.

In addition to their role in desensitization and internalization of G protein-coupled receptors (GPCRs), β-arrestins are essential scaffolds linking GPCRs to Erk1/2 signaling. However, their role in GPCR-operated Erk1/2 activation differs between GPCRs and the underlying mechanism remains poorly characterized. Here, we show that activation of serotonin 5-HT receptors, which engage Erk1/2 pathway via a β-arrestin-dependent mechanism, promotes MEK-dependent β-arrestin2 phosphorylation at Thr, a necessary step for Erk recruitment to the receptor/β-arrestin complex and Erk activation.

Eculizumab epitope on complement C5: Progress towards a better understanding of the mechanism of action.

Eculizumab is an anti-complement C5 monoclonal antibody which has greatly improved the prognosis and outcomes of nocturnal paroxysmal hemoglobinuria and atypical hemolytic and uremic syndromes. It is also known to be very species-specific for human C5, despite an important degree of conservation of the targeted macroglobulin domain, MG7, with that of other primates. However, the published eculizumab linear epitope does not explain this species specificity.

Role of Cysteine Residues in the Carboxyl-Terminus of the Follicle-Stimulating Hormone Receptor in Intracellular Traffic and Postendocytic Processing.

Posttranslational modifications occurring during the biosynthesis of G protein-coupled receptors include glycosylation and palmitoylation at conserved cysteine residues located in the carboxyl-terminus of the receptor. In a number of these receptors, these modifications play an important role in receptor function and particularly, in intracellular trafficking. In the present study, the three cysteine residues present in the carboxyl-terminus of the human FSHR were replaced with glycine by site-directed mutagenesis.

Assessing Gonadotropin Receptor Function by Resonance Energy Transfer-Based Assays.

Gonadotropin receptors belong to the super family of G protein-coupled receptors and mediate the physiological effects of follicle-stimulating hormone (FSHR) and luteinizing hormone (LHR). Their central role in the control of reproductive function has made them the focus of intensive studies. Upon binding to their cognate hormone, they trigger complex signaling and trafficking mechanisms that are tightly regulated in concentration, time, and space.

Biased signalling in follicle stimulating hormone action.

Follicle-stimulating hormone (FSH) plays a crucial role in the control of reproduction by specifically binding to and activating a membrane receptor (FSHR) that belongs to the G protein-coupled receptor (GPCR) family. Similar to all GPCRs, FSHR activation mechanisms have generally been viewed as a two-state process connecting a unique FSH-bound active receptor to the Gs/cAMP pathway. Over the last decade, paralleling the breakthroughs that were made in the GPCR field, our understanding of FSH actions at the molecular level has dramatically changed.

Integrating microRNAs into the complexity of gonadotropin signaling networks.

Follicle-stimulating hormone (FSH) is a master endocrine regulator of mammalian reproductive functions. Hence, it is used to stimulate folliculogenesis in assisted reproductive technologies (ART), both in women and in breeding animals. However, the side effects that hormone administration induces in some instances jeopardize the success of ART.

Competing G protein-coupled receptor kinases balance G protein and β-arrestin signaling.

Seven-transmembrane receptors (7TMRs) are involved in nearly all aspects of chemical communications and represent major drug targets. 7TMRs transmit their signals not only via heterotrimeric G proteins but also through β-arrestins, whose recruitment to the activated receptor is regulated by G protein-coupled receptor kinases (GRKs). In this paper, we combined experimental approaches with computational modeling to decipher the molecular mechanisms as well as the hidden dynamics governing extracellular signal-regulated kinase (ERK) activation by the angiotensin II type 1A receptor (AT(1A)R) in human embryonic kidney (HEK)293 cells.

Proteasome inhibitor-induced apoptosis in acute myeloid leukemia: a correlation with the proteasome status.

The proteasome plays a critical role in the regulation of many cellular processes, including the cell cycle and tumor growth. The proteasome inhibitor bortezomib has recently been approved for the treatment of relapsed and refractory multiple myeloma. In this study, we investigated the induction of apoptosis by proteasome inhibitors in several human acute myeloid leukemia (AML) cell lines and in primary cells from patients.

Specific plasma membrane protein phenotype of culture-amplified and native human bone marrow mesenchymal stem cells.

We have studied the plasma membrane protein phenotype of human culture-amplified and native bone marrow mesenchymal stem cells (BM MSCs). We have found, using microarrays and flow cytometry, that cultured cells express specifically 113 transcripts and 17 proteins that were not detected in hematopoietic cells. These antigens define a lineage-homogenous cell population of mesenchymal cells, clearly distinct from the hematopoietic lineages, and distinguishable from other cultured skeletal mesenchymal cells (periosteal cells and synovial fibroblasts).

The role of platelet/endothelial cell adhesion molecule 1 (CD31) and CD38 antigens in marrow microenvironmental retention of acute myelogenous leukemia cells.

In acute myelogenous leukemia (AML), leukemic cell-microenvironment interactions within various niches (stromal/osteoblastic or sinusoidal endothelial cell niches) have a role in leukemia cell survival and drug resistance. The AML leukemic cells express platelet/endothelial cell adhesion molecule-1 (CD31) and CD38, two adhesion molecules that could interact with microenvironmental elements, i.e.

The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities.

Adult bone marrow (BM)-derived stem cells, including hematopoietic stem cells (HSCs) and MSCs, represent an important source of cells for the repair of a number of damaged tissues. In contrast to HSCs, the soluble factors able to induce MSC migration have not been extensively studied. In the present work, we compared the in vitro migration capacity of human BM-derived MSCs, preincubated or not with the inflammatory cytokines interleukin 1beta (IL1beta) and tumor necrosis factor alpha (TNFalpha), in response to 16 growth factors (GFs) and chemokines.

Synthesis and biological evaluation of 7-azaindole derivatives, synthetic cytokinin analogues.

Cytokinins, N6-substituted adenine derivatives, are plant hormones playing important roles in various processes in plant development. Furthermore, cytokinins and their derivatives are able to control mammalian cell apoptosis and differentiation. The aim of our study was the synthesis of 7-azaindole derivatives as cytokinin analogues with the Hartwig-Buchwald coupling reaction in order to evaluate their biological properties on human myeloblastic leukaemia cells (HL-60 cell line).