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PubMed2001

Controlled trial of the effects of milk basic protein (MBP) supplementation on bone metabolism in healthy adult women.

Milk has more beneficial effects on bone health compared to other food sources. Recent in vitro and in vivo studies showed that milk whey protein, especially its basic protein fraction, contains several components capable of both promoting bone formation and inhibiting bone resorption. However, the effects of milk basic protein (MBP) on bone metabolism of humans are not known. The object of this study was to examine the effects of MBP on bone metabolism of healthy adult women. Thirty-three normal healthy women were randomly assigned to treatment with either placebo or MBP (40 mg per day) for six months. The bone mineral density (BMD) of the left calcaneus of each subject was measured at the beginning of the study and after six months of treatment, by dual-energy x-ray absorptiometry. Serum and urine indices of bone metabolism were measured at the base line, three-month intervals, and the end of the study. Daily intake of nutrients was monitored by a three-day food record made at three and six months. The mean (+/- SD) rate of left calcaneus BMD gain of women in the MBP group (3.42 +/- 2.05%) was significantly higher than that of women in the placebo group (2.01 +/- 1.75%, P = 0.042). As compared with the placebo group, urinary cross-linked N-teleopeptides of type-I collagen/creatinine and deoxypyridinoline/creatinine were significantly decreased in the MBP group (p < 0.05), while no significant differences between the two groups were observed in serum osteocalcin and bone-specific alkaline phosphatase concentrations. A daily MBP supplementation of 40 mg in healthy adult women can significantly increase their BMD independent of dietary intake of minerals and vitamins. This increase in BMD might be primarily mediated through inhibition of osteoclast-mediated bone resorption by the MBP supplementation.

Absorptiometry, Photon↗
PubMed1986

[MBP and GFAP immunohistochemistry of oligodendrogliomas with relationship to myelin-forming glia in cell differentiation].

The histologic feature of oligodendroglioma is constituted by the monotonously arranged sheets of tumor cells intersected with delicate vascular stroma. The shape of the tumor cells is usually uniform and occasionally rather pleomorphic. In order to clarify biological characteristics of the tumor cells at level of cell differentiation, immunohistochemical stains for myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) with PAP method were performed on 13 oligodendrogliomas obtained by surgical removal. The cells stained positive with MBP immunostain were encountered in 5 tumors and their incidence was ranging from 1% to more than 30% of all tumor cells. The MBP-positive cells were characterized by having a large clear nucleus with a prominent nucleolus and relatively abundant cytoplasm, that seemed to mimic myelin-forming glia appearing in normal developing brain. The cells with poor cytoplasm or surrounded by a perinuclear halo were MBP-negative, and the pleomorphic cells in majority of anaplastic oligodendrogliomas were also negative. On the other hand, with GFAP stain the positive cells were observed in 8 tumors. It is still controversial to interpret the occurrence of GFAP-positive cells in oligodendrogliomas. In this study the GFAP-positive cells were morphologically identical to the MBP-positive cells, so that both MBP and GFAP are supposed to exist in the same tumor cells. It is assumed that some of oligodendroglioma cells which showed such immunostainabilities could possess an intrinsic character to express a phenotype of myelin-forming glia. Possibly, MBP substance is applicable as one of immunohistochemical markers for oligodendroglioma cells to indicate a certain cell differentiation.

Adult↗
PubMed1995

Two mechanisms of antigen-specific apoptosis of myelin basic protein (MBP)-specific T lymphocytes derived from multiple sclerosis patients and normal individuals.

Several stimuli induce mature T cells to undergo apoptosis or programmed cell death (PCD) including specific Ag. We have demonstrated previously that Ag induces the death of encephalitogenic T cells in vitro and deletion in vivo, leading to amelioration of autoimmune encephalomyelitis. We have now examined whether activated, myelin basic protein (MBP)-specific human T cells may be eliminated by Ag-induced PCD. We demonstrate that activated MBP-specific T cell lines (TCL) undergo the classic nuclear morphologic changes and DNA fragmentation characteristic of apoptosis when given a TCR challenge. We found evidence that two mechanisms led to apoptosis: a propriocidal mechanism that was highly Ag-specific and dependent on the dose of exogenously added rIL-2, and a cytolytic mechanism in which MBP-specific TCL lysed B cell targets and engaged in considerable "fratricidal" cytolysis of other MBP-specific T cells. These two pathways leading to MBP-specific apoptotic death could be distinguished by their glucocorticoid sensitivity. Glucocorticoid treatment significantly blocked MBP-induced propriocidal apoptosis but had no effect on T cell cytolysis of B cell targets. Although it has been proposed that autoimmune disease could result from the failure of normal deletional mechanisms, this preliminary survey of MBP-reactive mature TCL from multiple sclerosis patients revealed that such cells are highly susceptible to TCR-induced PCD and comparable with TCL from normal subjects. Thus, therapeutic strategies based on Ag-induced PCD of T lymphocytes may be feasible in man.

Apoptosis↗
PubMed1993

Structure and developmental regulation of Golli-mbp, a 105-kilobase gene that encompasses the myelin basic protein gene and is expressed in cells in the oligodendrocyte lineage in the brain.

We have identified a novel transcription unit of 105 kilobases (called the Golli-mbp gene) that encompasses the mouse myelin basic protein (MBP) gene. Three unique exons within this gene are alternatively spliced into MBP exons and introns to produce a family of MBP gene-related mRNAs that are under individual developmental regulation. These mRNAs are temporally expressed within cells of the oligodendrocyte lineage at progressive stages of differentiation. Thus, the MBP gene is a part of a more complex gene structure, the products of which may play a role in oligodendrocyte differentiation prior to myelination. One Golli-mbp mRNA that encodes a protein antigenically related to MBP is also expressed in the spleen and other non-neural tissues.

Alternative Splicing↗
PubMed1996

[The serum MBP, myelin sheath immunohistochemistry and electromicroscope of expetrimental epilepsy rats].

We detected the level of myelin basic protein (MBP) in the serum of experimental epilepsy rats using simplified MBP ELISA, and the myelin sheaths of their brain with MBP immuno-histochemistry (IHC) and transmitted electronmicroscopy (TEM) in order to explore the relation of brain myelin sheaths and MBP to the pathogenic mechanism of epileptic seizure. The results show that the serum MBP level in the experimental epilepsy group is significantly higher than that in the control groups (P < 0.05), and is similar to that in some patients with generalized myoclonic seizures reported by us previously. The IHC and TEM findings in the brain of epilepsy rats indicate that the lamelliform structure of myelin sheaths in some part of hippocampus region becomes relaxing, disorderly and homogenized. Our studies imply that epileptic seizures are associated with MBP release from the subtle damaged regions of myelin sheaths during epileptic seizures, and the change of MBP component in myelin sheath may play and important role in the pathogenesis of epilepsy.

Animals↗
PubMed2000

Decrypting the spectrum of antigen-specific T-cell responses: the avidity repertoire of MBP-specific T-cells.

Myelin basic protein (MBP) is a well-characterized autoantigen potentially involved in the pathogenesis of the most common human demyelinating disease of the central nervous system (CNS), multiple sclerosis (MS). It is known that MBP-specific T-cell responses differ widely among different individuals and also within a single donor in terms of fine specificity and functional characteristics including the avidity in antigen recognition. In this report, we demonstrate that the in vitro selection of MBP-reactive T-cell repertoire is strictly dependent upon the antigen dose used in the primary cultures. MBP-specific T-cell lines (TCLs) were generated from MS patients and healthy donors using different antigen concentration in cultures (0.1 to 50 microg/ml). In both MS patients and controls, the number of obtained T-cell lines was affected by the antigen concentration. In addition, low and high antigen concentrations selected in vitro different T-cell populations in terms of peptide specificity patterns and different functional avidities in antigen recognition. Low concentrations of MBP in the primary cultures yielded a small number of TCLs recognizing the specific antigen with higher avidity whereas high antigen concentrations allowed the in vitro expansion of a higher numbers of T-cells recognizing MBP with lower avidity. The use of different antigen concentrations in the primary cultures can be applied as a simple experimental system to investigate the overall avidity repertoire of antigen-specific T-cell response in humans.

Antibody Affinity↗
PubMed1989

Human T lymphocyte response to myelin basic protein: selection of T lymphocyte lines from MBP-responsive donors.

The goal of this study was to delineate the importance of blood T lymphocyte responses to several myelin basic protein (MBP) preparations in the ultimate selection of MBP-specific T lymphocyte lines. Proliferation responses to human myelin basic protein (MBP) were assessed in blood samples from 27 multiple sclerosis (MS) patients, 20 patients with other neurologic diseases (OND), and 26 normal subjects, using five MBP preparations with different histories and electrophoretic characteristics to enhance the spectrum of epitopes represented. Substantial variations were observed in the ability of different MBP preparations to induce blood T cell proliferation in a given donor. However, four out of five of the MBPs induced modest but significant proliferation in the MS study population relative to normal individuals, with intermediate responses occurring in OND patients. Positive responses occurred more frequently in MS patients (78%) than in normal donors (31%), and were an important prerequisite for the successful selection of MBP-specific T cell lines.

Adult↗
PubMed1999

MBP-1 physically associates with histone deacetylase for transcriptional repression.

MBP-1, a c-myc promoter binding protein, is a mammalian transcription factor with intriguing properties including transcriptional repression of cellular genes. Recently, we have identified and characterized two different repressor domains of MBP-1. In this report, we have demonstrated that MBP-1 physically associates with histone deacetylase (HDAC), thus promoting formation of neucleosomes that inhibit transcription. Trichostatin A, an inhibitor of histone deacetylase, significantly reduces MBP-1-mediated transcriptional repression. However, MBP-1-mediated repression on c-myc promoter is resistant to histone deacetylase activity. Our results suggest that MBP-1 represses transcription by recruiting histone deacetylase as one of the mechanisms, whereas the other mechanism is resistant to HDAC activity and probably related to direct binding of promoter sequences or interaction through yet unidentified factor.

3T3 Cells↗
PubMed1994

Repertoire of rat MBP-reactive T cells: DNA sequencing analysis further demonstrates the clonal heterogeneity of rat T cells reactive against encephalitogenic epitopes.

Reports of the expression of very similar TCR structures by disparate rodent encephalitogenic T cells reactive with regions of MBP have aroused much interest for both theoretical and practical reasons. To ascertain the extent to which structural requirements of epitope recognition constrain TCR expression by MBP-reactive T cells, we set out to estimate the size of the overall repertoire of TCR beta-chain V beta-D beta-J beta (VDJ) assemblies in T cells of Lewis rats specific for MBP(68-88) as well as those specific for MBP(87-99). We previously reported that such T cells can express a diversity of V beta genes as revealed by PCR analysis. In this study, we have used direct sequencing of PCR products amplified from encephalitogenic T-cell clones and pauciclonal T-cell lines to demonstrate that VDJ structures of the rat T cells specific for either residues 68 to 88 or 87 to 99 of MBP are highly heterogeneous. Our results showed that (1) no pattern is evident in the utilization of germline J gene segments by individual T-cell clones; from a total of over 100 successfully sequenced clones displaying in-frame rearrangements, all the J beta segments have been demonstrated. (2) Even among the T-cell clones which share the V beta expression, J beta is variable. (3) Due to joining variations between the V beta, D beta, and J beta gene segments, no two of the T-cell clones examined share entire VDJ structures. Our study is the first report of nucleotide and amino acid sequences of TCR beta-chains from rat encephalitogenic T cells expressing V beta genes other than V beta 8.2. It demonstrates that the TCR repertoire of the MBP-reactive as well as encephalitogenic T cells is heterogeneous, even though a certain T-cell subset frequently dominated by the mechanism needs to be clarified.

Amino Acid Sequence↗
PubMed1985

Dose-dependency of MBP-induced demyelination in the guinea pig.

The pathology of experimental allergic encephalomyelitis (EAE) induced by bovine myelin basic protein (MBP) has been examined in the guinea pig with a series of doses ranging from 37.5 micrograms to 600 micrograms. This was to investigate whether the previously demonstrated lack of demyelinative effect by MBP was dose-related. At all doses tested, MBP induced clinical disease. Inflammation was the major feature of lesions in all animals. However, no demyelination was seen when 75 micrograms MBP or less was given. At higher doses (150 micrograms upwards), MBP always induced intense inflammation but demyelination was encountered inconsistently. These observations support the contention that in addition to an immune response to MBP, other factors contribute to autoimmune demyelination.

Animals↗
PubMed2004

High-yield expression and purification of p18 form of Bax as an MBP-fusion protein.

Bax is a pro-apoptotic member of the Bcl-2 family of proteins, which is present in the cytosol of various types of cells in full-length form (p21 Bax). During apoptosis, the N-terminal truncated version of Bax (p18 Bax) is often formed via cleavage of the p21 Bax by the calcium-dependent enzyme, calpain. p18 Bax is a membrane protein found primarily in the mitochondrial fraction of apoptotic cells. Although noticeable amounts of p18 Bax appear relatively late in apoptosis, it may still play a role in the apoptotic cascade. The role of p18 Bax in the apoptotic cascade, particularly, in the release of cytochrome c from mitochondria has not been studied. The goal of this study was to produce reasonable amounts of p18 Bax and study its effect on isolated mitochondria. The expression and purification of membrane proteins such as p18 Bax represents a substantial challenge due to insolubility. We report here that the apoptotic form of Bax, p18 Bax, is highly soluble in the absence of detergents upon fusion with maltose-binding protein (MBP). We describe a scheme for expression and simple metal-affinity based purification of MBP-p18Bax. The MBP-p18Bax triggers the release of cytochrome c from isolated mitochondria in a concentration-dependent, Bcl-2-sensitive manner. The MBP tag of the MBP-p18Bax can be cleaved off with 3C protease to produce pure p18 Bax, although the solubility of p18 Bax becomes very limited. The highly soluble, MBP-fused form of p18 Bax provides a convenient tool to study this apoptotic form of Bax protein.

Animals↗
PubMed2006

Formation of well-defined soluble aggregates upon fusion to MBP is a generic property of E6 proteins from various human papillomavirus species.

Protein aggregation is a main barrier hindering structural and functional studies of a number of interesting biological targets. The E6 oncoprotein of Human Papillomavirus strain 16 (E6(16)) is difficult to express under a native soluble form in bacteria. Produced as an unfused sequence, it forms inclusion bodies. Fused to the C-terminus of MBP, it is mainly produced in the form of soluble high molecular weight aggregates. Here, we produced as MBP-fusions seven E6 proteins from other HPV strains (5, 11, 18, 33, 45, 52, and 58) belonging to four different species, and we compared their aggregation state to that of MBP-E6(16). Using a fast mutagenesis method, we changed most non-conserved cysteines to the isosteric residue serine to minimize disulfide bridge-mediated aggregation during purification. Static and dynamic light scattering measurements, ultracentrifugation and electron microscopy demonstrated the presence in all MBP-E6 preparations of soluble high-molecular weight aggregates with a well-defined spherical shape. These aggregated particles are relatively monodisperse but their amount and their size vary depending on the conditions of expression and the strain considered. For all strains, minimal aggregate formation occurs when the expression is performed at 15 degrees C. Such observations suggest that the assembly of MBP-E6 aggregates takes place in vivo during protein biosynthesis, rather than occurring during purification. Finally, we show that all MBP-E6 preparations contain two zinc ions per protein monomer, suggesting that E6 domains within the high molecular weight aggregates possess a native-like fold, which enables correct coordination to the metal center.

Alphapapillomavirus↗
PubMed1998

Golli-MBP gene in multiple sclerosis susceptibility.

Multiple sclerosis (MS) is an oligo- or polygenic disease but no specific susceptibility genes have been identified so far. In the Finnish population we have previously found evidence for linkage between MS and the myelin basic protein gene (here called Golli-MBP gene) suggesting that either Golli-MBP or another gene in its vicinity contributes to MS suceptibility. Here we have screened the Golli-MBP gene for nucleotide variations and carried out multipoint association analyses in a Finnish case-control data-set as well as in an independent data-set composed of 151 MS families from Finland and Sweden. In both data-sets we found association between MS and alleles in the 1.27 kilobase (kb) range at a tetranucleotide repeat element (TGGA)n which is located 1 kb upstream of the MBP exon 1. Haplotype analyses suggested that the MS-associated 1.27 kb alleles can be split into predisposing and non-predisposing variants and provided evidence that the candidate DNA region contributing to MS susceptibility should be located at the Golli-MBP gene within a 20-25 kb segment that was conserved in the predisposing haplotypes. These findings suggest a role for the Golli-MBP locus in MS susceptibility, at least in a subset of patients, and serve as a basis for highly focused attempts to identify predisposing mutation(s).

Adult↗
PubMed2003

Analysis of the cruciform binding activity of recombinant 14-3-3zeta-MBP fusion protein, its heterodimerization profile with endogenous 14-3-3 isoforms, and effect on mammalian DNA replication in vitro.

The human cruciform binding protein (CBP), a member of the 14-3-3 protein family, has been recently identified as an origin of DNA replication binding protein and involved in DNA replication. Here, pure recombinant 14-3-3zeta tagged with maltose binding protein (r14-3-3zeta-MBP) at its N-terminus was tested for binding to cruciform DNA either in the absence or presence of F(TH), a CBP-enriched fraction, by electromobility shift assay (EMSA), followed by Western blot analysis of the electroeluted CBP-cruciform DNA complex. The r14-3-3zeta-MBP was found to have cruciform binding activity only after preincubation with F(TH). Anti-MBP antibody immunoprecipitation of F(TH) preincubated with r14-3-3zeta-MBP, followed by Western blot analysis with antibodies specific to the beta, gamma, epsilon, zeta, and sigma 14-3-3 isoforms showed that r14-3-3zeta-MBP heterodimerized with the endogenous beta, epsilon, and zeta isoforms present in the F(TH) but not with the gamma or sigma isoforms. Immunoprecipitation of endogenous 14-3-3zeta from nuclear extracts (NE) of HeLa cells that were either serum-starved (s-s) or blocked at the G(1)/S or G(2)/M phases of the cell cycle revealed that at G(1)/S and G(2)/M, the zeta isoform heterodimerized only with the beta and epsilon isoforms, while in s-s extracts, the 14-3-3zeta/epsilon heterodimer was never detected, and the 14-3-3zeta/beta heterodimer was seldom detected. Furthermore, addition of r14-3-3zeta-MBP to HeLa cell extracts used in a mammalian in vitro replication system increased the replication level of p186, a plasmid bearing the minimal 186-bp origin of the monkey origin of DNA replication ors8, by approximately 3.5-fold. The data suggest that specific dimeric combinations of the 14-3-3 isoforms have CBP activity and that upregulation of this activity leads to an increase in DNA replication.

14-3-3 Proteins↗
PubMed2004

Superoxide production from human polymorphonuclear leukocytes by human mannan-binding protein (MBP).

Mannan-binding protein (MBP) is a Ca(2+)-dependent mammalian lectin that plays an important role in innate immunity. In this study, we found that ligand-bound MBP stimulates polymorphonuclear leukocytes (PMN) to induce cell aggregation and superoxide production. The biological response of PMN to ligand-bound MBP was dose- and time-dependent. The PMN aggregation and superoxide production induced by ligand-bound MBP was blocked completely by pertussis toxin, and partially blocked by a platelet activation factor receptor antagonist, TCV-309. These findings suggest that the ligand-bound MBP stimulates PMN through a putative MBP receptor(s) on PMN.

Calcium↗
PubMedDate not supplied

Role of mannan-binding protein, MBP, in innate immunity.

Mannan-binding protein (MBP) is a C-type lectin, which binds to carbohydrates on the surface of some microorganisms and kills them through the activation of complement. This complement activation pathway is called the lectin pathway. MBP also kills mammalian cells that express MBP ligands on their surfaces via the lectin pathway. Recently, we found anti-tumor activity of MBP in vivo using tumor cells transplanted into nude mice. We propose to call this anti-tumor effect mannan-binding protein-dependent cell-mediated cytotoxicity (MDCC), because it does not require complement activation, and the involvement of some immune cells was assumed. Very recently, MBP was demonstrated to be selectively expressed in epithelial cells of the small intestine. This finding may suggest that MBP plays an important role in the small intestine as a host defense factor.

Animals↗
PubMed2006

[Prevention of osteoporosis by foods and dietary supplements. Milk basic protein (MBP) induces alveolar bone formation in rat experimental periodontitis].

Periodontitis is a chronic inflammatory disease caused by infection of periodontopathic bacteriae, which induced alveolar bone resorpotion. Milk basic protein (MBP) has been reported to be useful as a supplement because of increasing bone formation in animal and human studies. We examined the effect of MBP for alveolar bone formation in rat experimental periodontitis. After alveolar bone resorption was induced by ligature technique, the diets containing low and high dose of MBP were given to rats for 90 days. Micro-focus computed tomography and histological observation revealed a recovery of alveolar bone in high-dose MBP group compared to the control group. Osteoid thickness of alveolar bone crest significantly increased in low and high-dose MBP groups. These findings indicate that MBP may be effective for the recovery of alveolar bone resorption in periodontitis.

Alveolar Bone Loss↗
PubMed2000

Immunogenicity of self antigens is unrelated to MHC-binding affinity: T-cell determinant structure of Golli-MBP in the BALB/c mouse.

The 'classical' myelin basic protein (MBP) exons belong to a much larger unit, termed the 'Golli-MBP' gene. Here we have examined the T-cell determinant structure of the Golli protein region in the BALB/c mouse. Golli p10-24, which was shown to have the strongest affinity for I-A(d), could not induce T-cell activation. Paradoxically, the poorer binding, overlapping p5-19 was effective at inducing T-cell proliferation. Thus, immunogenicity is not necessarily related to the MHC-binding affinity of self-peptides. In addition, MBP: p151-168-specific T cell clones responded only poorly to J37, a Golli-MBP protein, while MBP: 59-76-specific clones responded well to J37.

Amino Acid Sequence↗