Richard Bucala

Bio: Richard Bucala is an academic researcher from Yale University. The author has contributed to research in topics: Macrophage migration inhibitory factor & Cytokine. The author has an hindex of 119, co-authored 595 publications receiving 54607 citations. Previous affiliations of Richard Bucala include École Polytechnique Fédérale de Lausanne & Rockefeller University.

An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: Role in tumor cell glycolysis and the Warburg effect

Abstract: Cancer cells maintain a high glycolytic rate even in the presence of oxygen, a phenomenon first described over 70 years ago and known historically as the Warburg effect. Fructose 2,6-bisphosphate is a powerful allosteric regulator of glycolysis that acts to stimulate the activity of 6-phosphofructo-1-kinase (PFK-1), the most important control point in mammalian glycolysis. The steady state concentration of fructose 2,6-bisphosphate in turn depends on the activity of the enzyme 6-phosphofructo-2-kinase (PFK-2)/fructose-2,6-bisphosphatase, which is expressed in several tissue-specific isoforms. We report herein the identification of a gene product for this enzyme that is induced by proinflammatory stimuli and which is distinguished by the presence of multiple copies of the AUUUA mRNA instability motif in its 3′-untranslated end. This inducible gene for PFK-2 is expressed constitutively in several human cancer cell lines and was found to be required for tumor cell growth in vitro and in vivo. Inhibition of inducible PFK-2 protein expression decreased the intracellular level of 5-phosphoribosyl-1-pyrophosphate, a product of the pentose phosphate pathway and an important precursor for nucleic acid biosynthesis. These studies identify a regulatory isoenzyme that may be essential for tumor growth and provide an explanation for long-standing observations concerning the apparent coupling of enhanced glycolysis and cell proliferation.

The role of circulating fibrocytes in fibrosis.

Abstract: Fibrocytes are cells that circulate in the peripheral blood and produce connective tissue proteins such as vimentin and collagens I and III. Fibrocytes are associated with skin lesions, pulmonary fibrosis, and tumors and they contribute to the remodeling response by secreting matrix metalloproteinases. Fibrocytes can further differentiate, and they are a likely source of the contractile myofibroblast that appears in many fibrotic lesions. There is evidence in the skin for a prominent role for fibrocytes in the development of hypertrophic scars and keloids. In asthma or in experimental models of pulmonary fibrosis, fibrocytes have been shown to infiltrate areas of inflammation and tissue damage. Fibrocytes constitute part of the stromal response to tumor invasion, and there is evidence that these cells may be a prognosticator of malignant potential. IL-1, TGF-beta, chemokines, and serum amyloid P modulate the appearance and function of fibrocytes. Fibrocytes themselves produce inflammatory cytokines, growth factors, and chemokines. The intercellular signals that modulate fibrocyte trafficking, proliferation, and differentiation are only partially defined, but a better understanding of these signals enable new therapies to prevent pathologic fibrosis or to improve the tissue repair response.

The p53-dependent effects of macrophage migration inhibitory factor revealed by gene targeting

Abstract: Macrophage migration inhibitory factor (MIF) is a mediator of host immunity and functions as a high, upstream activator of cells within the innate and the adaptive immunological systems. Recent studies have suggested a potentially broader role for MIF in growth regulation because of its ability to antagonize p53-mediated gene activation and apoptosis. To better understand MIF's activity in growth control, we generated and characterized a strain of MIF-knockout (MIF-KO) mice in the inbred, C57BL/6 background. Embryonic fibroblasts from MIF-KO mice exhibit p53-dependent growth alterations, increased p53 transcriptional activity, and resistance to ras-mediated transformation. Concurrent deletion of the p53 gene in vivo reversed the observed phenotype of cells deficient in MIF. In vivo studies showed that fibrosarcomas induced by the carcinogen benzo[alpha]pyrene are smaller in size and have a lower mitotic index in MIF-KO mice relative to their WT counterparts. The data provide direct genetic evidence for a functional link between MIF and the p53 tumor suppressor and indicate an important and previously unappreciated role for MIF in carcinogenesis.

Hemoglobin-AGE: a circulating marker of advanced glycosylation

Abstract: Advanced glycosylation end products (AGEs) form spontaneously from glucose-derived Amadori products and accumulate on long-lived tissue proteins. AGEs have been implicated in the pathogenesis of several of the complications of aging and diabetes, including atherosclerosis and renal disease. With the use of recently developed AGE-specific antibodies, an AGE-modified form of human hemoglobin has been identified. Termed hemoglobin-AGE (Hb-AGE), this modified species accounts for 0.42 percent of circulating hemoglobin in normal individuals but increases to 0.75 percent in patients with diabetes-induced hyperglycemia. In a group of diabetic patients treated with the advanced glycosylation inhibitor aminoguanidine, Hb-AGE levels decreased significantly over a 1-month period. Hemoglobin-AGE measurements may provide an index of long-term tissue modification by AGEs and prove useful in assessing the contribution of advanced glycosylation to a variety of diabetic and age-related complications.

An essential role for macrophage migration inhibitory factor in the tuberculin delayed-type hypersensitivity reaction

Abstract: 30 years ago, investigations into the molecular basis of the delayed-type hypersensitivity reaction (DTH) provided evidence for the first lymphokine activity: a lymphocyte-derived mediator called macrophage migration inhibitory factor (MIF), which inhibited the random migration of peritoneal macrophages. Despite the long-standing association of MIF with the DTH reaction and the cloning of a human protein with macrophage migration inhibitory activity, the precise role of MIF in this classic cell-mediated immune response has remained undefined. This situation has been further complicated by the fact that two other cytokines, interferon gamma and IL-4, similarly inhibit macrophage migration and by the identification of mitogenic contaminants in some preparations of cloned human MIF. Using recently developed molecular probes for mouse MIF, we have examined the role of this protein in a classical model of DTH, the tuberculin reaction in mice. Both MIF messenger RNA and protein were expressed prominently in DTH lesions, as assessed by reverse transcription polymerase chain reaction, in situ hybridization, and immunostaining with anti-MIF antibody. The predominant cellular origin of MIF appeared to be the monocyte/macrophage, a cell type identified recently to be a major source of MIF release in vivo. The administration of neutralizing anti-MIF antibodies to mice inhibited significantly the development of DTH, thus affirming the central role of MIF in this classic immunological response.

I and i

Abstract: There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality. Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

Multilineage Potential of Adult Human Mesenchymal Stem Cells

Abstract: Human mesenchymal stem cells are thought to be multipotent cells, which are present in adult marrow, that can replicate as undifferentiated cells and that have the potential to differentiate to lineages of mesenchymal tissues, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Cells that have the characteristics of human mesenchymal stem cells were isolated from marrow aspirates of volunteer donors. These cells displayed a stable phenotype and remained as a monolayer in vitro. These adult stem cells could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages. Individual stem cells were identified that, when expanded to colonies, retained their multilineage potential.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。