The VLA-4 integrin is constitutively active in circulating chronic lymphocytic leukemia cells via BCR autonomous signaling: a novel anchor-independent mechanism exploiting soluble blood-borne ligands.

In chronic lymphocytic leukemia (CLL), survival of neoplastic cells depends on microenvironmental signals at lymphoid sites where the crosstalk between the integrin VLA-4 (CD49d/CD29), expressed in ~40% of CLL, and the B-cell receptor (BCR) occurs. Here, BCR engagement inside-out activates VLA-4, thus enhancing VLA-4-mediated adhesion of CLL cells, which in turn obtain pro-survival signals from the surrounding microenvironment. We report that the BCR is also able to effectively inside-out activate the VLA-4 integrin in circulating CD49d-expressing CLL cells through an autonomous antigen-independent BCR signaling.

Metformin: A New Inhibitor of the Wnt Signaling Pathway in Cancer.

The biguanide drug metformin is widely used in type 2 diabetes mellitus therapy, due to its ability to decrease serum glucose levels, mainly by reducing hepatic gluconeogenesis and glycogenolysis. A considerable number of studies have shown that metformin, besides its antidiabetic action, can improve other disease states, such as polycystic ovary disease, acute kidney injury, neurological disorders, cognitive impairment and renal damage. In addition, metformin is well known to suppress the growth and progression of different types of cancer cells both in vitro and in vivo.

Methylglyoxal Impairs the Pro-Angiogenic Ability of Mouse Adipose-Derived Stem Cells (mADSCs) via a Senescence-Associated Mechanism.

Adipose-derived stem cells (ADSCs) play a crucial role in angiogenesis and repair of damaged tissues. However, in pathological conditions including diabetes, ADSC function is compromised. This work aims at evaluating the effect of Methylglyoxal (MGO), a product of chronic hyperglycemia, on mouse ADSCs' (mADSCs) pro-angiogenic function and the molecular mediators involved.

Rheumatoid factor IgM autoantibodies control IgG homeostasis.

Rheumatoid arthritis is an autoimmune disease characterized by joint inflammation due to autoantibodies targeting multiple self-proteins. Most patients with poor prognosis show elevated titers of IgM antibodies specifically binding to IgG. Such autoreactive antibodies are referred to as rheumatoid factor (RF).

Glyoxalase 1 knockdown induces age-related β-cell dysfunction and glucose intolerance in mice.

Tight control of glycemia is a major treatment goal for type 2 diabetes mellitus (T2DM). Clinical studies indicated that factors other than poor glycemic control may be important in fostering T2DM progression. Increased levels of methylglyoxal (MGO) associate with complications development, but its role in the early steps of T2DM pathogenesis has not been defined.

Autoreactive antibodies control blood glucose by regulating insulin homeostasis.

Homeostasis of metabolism by hormone production is crucial for maintaining physiological integrity, as disbalance can cause severe metabolic disorders such as diabetes mellitus. Here, we show that antibody-deficient mice and immunodeficiency patients have subphysiological blood glucose concentrations. Restoring blood glucose physiology required total IgG injections and insulin-specific IgG antibodies detected in total IgG preparations and in the serum of healthy individuals.

The Determinants of B Cell Receptor Signaling as Prototype Molecular Biomarkers of Leukemia.

Advanced genome-wide association studies (GWAS) identified several transforming mutations in susceptible loci which are recognized as valuable prognostic markers in chronic lymphocytic leukemia (CLL) and B cell lymphoma (BCL). Alongside, robust genetic manipulations facilitated the generation of preclinical mouse models to validate mutations associated with poor prognosis and refractory B cell malignancies. Taken together, these studies identified new prognostic markers that could achieve characteristics of precision biomarkers for molecular diagnosis.

B cell receptor isotypes differentially associate with cell signaling, kinetics, and outcome in chronic lymphocytic leukemia.

In chronic lymphocytic leukemia (CLL), the B cell receptor (BCR) plays a critical role in disease development and progression, as indicated by the therapeutic efficacy of drugs blocking BCR signaling. However, the mechanism(s) underlying BCR responsiveness are not completely defined. Selective engagement of membrane IgM or IgD on CLL cells, each coexpressed by more than 90% of cases, leads to distinct signaling events.

An optimized derivative of an endogenous CXCR4 antagonist prevents atopic dermatitis and airway inflammation.

Aberrant CXCR4/CXCL12 signaling is involved in many pathophysiological processes such as cancer and inflammatory diseases. A natural fragment of serum albumin, named EPI-X4, has previously been identified as endogenous peptide antagonist and inverse agonist of CXCR4 and is a promising compound for the development of improved analogues for the therapy of CXCR4-associated diseases. To generate optimized EPI-X4 derivatives we here performed molecular docking analysis to identify key interaction motifs of EPI-X4/CXCR4.

The Dual-Role of Methylglyoxal in Tumor Progression - Novel Therapeutic Approaches.

One of the hallmarks of cancer cells is their metabolic reprogramming, which includes the preference for the use of anaerobic glycolysis to produce energy, even in presence of normal oxygen levels. This phenomenon, known as "Warburg effect", leads to the increased production of reactive intermediates. Among these Methylglyoxal (MGO), a reactive dicarbonyl known as the major precursor of the advanced glycated end products (AGEs), is attracting great attention.

is an inherited risk factor for CLL through the acquisition of a single-point mutation enabling autonomous BCR signaling.

The prognosis of chronic lymphocytic leukemia (CLL) depends on different markers, including cytogenetic aberrations, oncogenic mutations, and mutational status of the immunoglobulin (Ig) heavy-chain variable (IGHV) gene. The number of IGHV mutations distinguishes mutated (M) CLL with a markedly superior prognosis from unmutated (UM) CLL cases. In addition, B cell antigen receptor (BCR) stereotypes as defined by IGHV usage and complementarity-determining regions (CDRs) classify ∼30% of CLL cases into prognostically important subsets.

Dicarbonyl Stress at the Crossroads of Healthy and Unhealthy Aging.

Dicarbonyl stress occurs when dicarbonyl metabolites (i.e., methylglyoxal, glyoxal and 3-deoxyglucosone) accumulate as a consequence of their increased production and/or decreased detoxification.

Nutritional Factors, DNA Methylation, and Risk of Type 2 Diabetes and Obesity: Perspectives and Challenges.

A healthy diet improves life expectancy and helps to prevent common chronic diseases such as type 2 diabetes (T2D) and obesity. The mechanisms driving these effects are not fully understood, but are likely to involve epigenetics. Epigenetic mechanisms control gene expression, maintaining the DNA sequence, and therefore the full genomic information inherited from our parents, unchanged.

Differences in Self-Recognition between Secreted Antibody and Membrane-Bound B Cell Antigen Receptor.

The random gene segment rearrangement during B cell development ensures Ab repertoire diversity. Because this process might generate autoreactive specificities, it has been proposed that stringent selection mechanisms prevent the development of autoreactive B cells. However, conventional assays to identify autoreactive B cells usually employ in vitro-generated Abs, which differ from membrane-bound BCRs.

Isotype Specific Assembly of B Cell Antigen Receptors and Synergism With Chemokine Receptor CXCR4.

Expression of the membrane-bound form of the immunoglobulin (Ig) as part of the antigen receptor is indispensable for both the development and the effector function of B cells. Among five known isotypes, IgM and IgD are the common B cell antigen receptors (BCRs) that are co-expressed in naïve B cells. Despite having identical antigen specificity and being associated with the same signaling heterodimer Igα/Igβ (CD79a/CD79b), IgM and IgD-BCR isotypes functionally differ from each other in the manner of antigen binding, the formation of isolated nanoclusters and in their interaction with co-receptors such as CD19 and CXCR4 on the plasma membrane.

Methylglyoxal accumulation de-regulates HoxA5 expression, thereby impairing angiogenesis in glyoxalase 1 knock-down mouse aortic endothelial cells.

Impaired angiogenesis leads to long-term complications and is a major contributor of the high morbidity in patients with Diabetes Mellitus (DM). Methylglyoxal (MGO) is a glycolysis byproduct that accumulates in DM and is detoxified by the Glyoxalase 1 (Glo1). Several studies suggest that MGO contributes to vascular complications through mechanisms that remain to be elucidated.