Mimicry between neurokinin-1 and fibronectin may explain the transport and stability of increased substance P immunoreactivity in patients with bone marrow fibrosis

Bone marrow (BM) fibrosis may occur in myeloproliferative diseases, lymphoma, myelodysplastic syndrome, myeloma, and infectious diseases. In this study, the role of substance P (SP), a peptide with pleiotropic functions, was examined. Some of its functions-angiogenesis, fibroblast proliferation, and stimulation of BM progenitors-are amenable to inducing BM fibrosis. Indeed, a significant increase was found in SP-immunoreactivity (SP-IR) in the sera of patients with BM fibrosis (n = 44) compared with the sera of patients with hematologic disorders and no histologic evidence of fibrosis (n = 46) (140 +/-12 vs 18 +/-3; P <.01). Immunoprecipitation of sera SP indicated that this peptide exists in the form of a complex with other molecule(s). It was, therefore, hypothesized that SP might be complexed with NK-1, its natural receptor, or with a molecule homologous to NK-1. To address this, 3 cDNA libraries were screened that were constructed from pooled BM stroma or mononuclear cells with an NK-1 cDNA probe. A partial clone (clone 1) was retrieved that was 97% homologous to the ED-A region of fibronectin (FN). Furthermore, sequence analyses indicated that clone 1 shared significant homology with exon 5 of NK-1. Immunoprecipitation and Western blot analysis indicated co-migration of SP and FN in 27 of 31 patients with BM fibrosis. Computer-assisted molecular modeling suggested that similar secondary structural features between FN and NK-1 and the relative electrostatic charge might explain a complex formed between FN (negative) and SP (positive). This study suggests that SP may be implicated in the pathophysiology of myelofibrosis, though its role would have to be substantiated in future research. (Blood. 2001;97:3025-3031)     

An elaborative NMR based plasma metabolomics study revealed metabolic derangements in patients with mild cognitive impairment: a study on north Indian population

Metabolic Brain Disease - Mild cognitive impairment (MCI) is transition phase between cognitive decline and dementia. The current study aims to investigate altered metabolic pattern in plasma of...     

Matrix composition regulates three-dimensional network formation by endothelial cells and mesenchymal stem cells in collagen/fibrin materials

Co-cultures of endothelial cells (EC) and mesenchymal stem cells (MSC) in three-dimensional (3D) protein hydrogels can be used to recapitulate aspects of vasculogenesis in vitro. MSC provide paracrine signals that stimulate EC to form vessel-like structures, which mature as the MSC transition to the role of mural cells. In this study, vessel-like network formation was studied using 3D collagen/fibrin (COL/FIB) matrices seeded with embedded EC and MSC and cultured for 7 days. The EC:MSC ratio was varied from 5:1, 3:2, 1:1, 2:3 and 1:5. The matrix composition was varied at COL/FIB compositions of 100/0 (pure COL), 60/40, 50/50, 40/60 and 0/100 (pure FIB). Vasculogenesis was markedly decreased in the highest EC:MSC ratio, relative to the other cell ratios. Network formation increased with increasing fibrin content in composite materials, although the 40/60 COL/FIB and pure fibrin materials exhibited the same degree of vasculogenesis. EC and MSC were co-localized in vessel-like structures after 7 days and total cell number increased by approximately 70%. Mechanical property measurements showed an inverse correlation between matrix stiffness and network formation. The effect of matrix stiffness was further investigated using gels made with varying total protein content and by crosslinking the matrix using the dialdehyde glyoxal. This systematic series of studies demonstrates that matrix composition regulates vasculogenesis in 3D protein hydrogels, and further suggests that this effect may be caused by matrix mechanical properties. These findings have relevance to the study of neovessel formation and the development of strategies to promote vascularization in transplanted tissues.     

Delayed differentiation of HL-60 cells following exposure to hypoxia

OBJECTIVE: Hemorrhagic shock and hypoxia have been shown to alter immune and hematopoietic functions. Cellular hypoxia is thought to be the primary defect and has been shown to induce a variety of biological alterations. In this study, we examined if this defect is at the stage of terminal differentiation with the myelomonocytic cell line HL-60. METHODS: After hypoxia, HL-60 cells were induced with 1.25% dimethyl sulfoxide (DMSO) to differentiate toward neutrophils (PMN). The ability to differentiate was evaluated by nitroblue tetrazolium staining. The function of the differentiated cells was determined by intracellular calcium levels after exposure to different chemotactic factors, and levels of Id-2 mRNA, a factor associated with terminal differentiation of myeloid cells, were assessed with Northern analysis. RESULTS: At 48 h following exposure to hypoxia, HL-60 differentiation was significantly blunted (hypoxia 51 +/- 1%, normoxia 69 +/- 1%; P < 0.001). Intracellular calcium levels in DMSO-treated cells stimulated with 1 microM bacterial tripeptide, fMLP, were significantly reduced in the hypoxic cells (381 +/- 11 nM vs 449 +/- 10 nM; P < 0.01). No difference was noted for two other chemotactic factors, C5a and platelet-activating factor. Using Northern analysis to determine the levels of Id-2 mRNA, we demonstrated that hypoxia reduced the levels by 20% over normoxic cells. CONCLUSION: This study demonstrates that hypoxia blunts the differentiation of HL-60 cells to PMN. This altered function of hypoxia appears to be reversible since hypoxia prolonged the time for HL-60 cells to differentiate and this may be partly explained by the premature downregulation of Id-2 expression.     

The Impact of Culturally Relevant Violence Prevention Models on School-Age Youth

The Family and Community Violence Prevention (FCVP) Program was established in 1994 to address the escalation of youth violence among ethnic minorities. This federally funded program adapted the public health model and organized Family Life Centers throughout the country to serve youth who were considered to be at risk for violence and other abusive behaviors. The purpose of this three-year study, 1999–2002, was to determine the effectiveness of the FCVP Program's six-component curriculum in reducing violence among participants. Results from posttest scores of 2,315 youth showed girls 12 and over to be most at risk for deviant behaviors; the program was most effective with boys under age 12. Academic performance and bonding to school were protective factors whereas exposure to violence was a risk factor for all four ethnic groups studied—African Americans, Hispanics, Native Americans, and Native Hawaiians. Editors' Strategic Implications: Cultural anthropologists, public health specialists, and school officials should know that prevention programs can be designed to reflect the unique, culturally appropriate norms of specific ethnic minority groups, even as these programs address shared risk factors. The authors discuss the promising strategy of enhancing academic performance and school bonding to serve as protective factors against school violence, but they also describe age, gender, and cultural differences that must be addressed in future research.     

Neurokinin receptors: relevance to the emerging immune system

The adult bone marrow (BM )is the major site of the emerging immune system. Hematopoiesis is the process whereby immune cells are generated from a finite number of hematopoietic stem cells. Hematopoiesis is regulated by soluble mediators and inter cellular interactions. A major regulatory mechanism of hematopoiesis involves bidirectional crosstalk with the neural system. This communication mainly occurs by the release of neurotransmitters from innervated fibers. The neurotransmitters interact with specific receptors on BM resident cells and release other hematopoietic regulators such as cytokines. Together, the neurotransmitters and cytokines form a complex network to regulate hematopoiesis. Among BM resident cells, the stromal cells are particularly relevant for two reasons:1) they represent non-neural sources of neurotransmitters, and 2) stromal cells express specific receptors for neurotransmitters. This review focuses on the hematopoietic effects of neurotransmitters belonging to the tachykinins. The two major tachykinins focused in this review are substance P and neurokinin (NK)-A,11 and 10 amino acid peptides. In BM, the tachykinins interact with two major NK receptors:NK-1 and NK-2.These two receptors appear to limit tachykinin-mediated effects on hematopoiesis. The central roles of NK receptors within a network comprising of cytokines and tachykinins are reviewed.