Extracellular matrix proteoglycans control the fate of bone marrow stromal cells

Extracellular matrix glycoproteins and proteoglycans bind a variety of growth factors and cytokines thereby regulating matrix assembly as well as bone formation. However, little is known about the mechanisms by which extracellular matrix molecules modulate osteogenic stem cells and bone formation. Using mice deficient in two members of the small leucine-rich proteoglycans, biglycan and decorin, we uncovered a role for these two extracellular matrix proteoglycans in modulating bone formation from bone marrow stromal cells. Our studies showed that the absence of the critical transforming growth factor-beta (TGF-beta)-binding proteoglycans, biglycan and decorin, prevents TGF-beta from proper sequestration within the extracellular matrix. The excess TGF-beta directly binds to its receptors on bone marrow stromal cells and overactivates its signaling transduction pathway. Overall, the predominant effect of the increased TGF-beta signaling in bgn/dcn-deficient bone marrow stromal cells is a "switch in fate" from growth to apoptosis, leading to decreased numbers of osteoprogenitor cells and subsequently reduced bone formation. Thus, biglycan and decorin appear to be essential for maintaining an appropriate number of mature osteoblasts by modulating the proliferation and survival of bone marrow stromal cells. These findings underscore the importance of the micro-environment in controlling the fate of adult stem cells and reveal a novel cellular and molecular basis for the physiological and pathological control of bone mass.     

Genetic diversity of chloroquine-resistant Plasmodium vivax parasites from the western Brazilian Amazon

The molecular basis of Plasmodium vivax chloroquine (CQ) resistance is still unknown. Elucidating the molecular background of parasites that are sensitive or resistant to CQ will help to identify and monitor the spread of resistance. By genotyping a panel of molecular markers, we demonstrate a similar genetic variability between in vitro CQ-resistant and sensitive phenotypes of P. vivax parasites. However, our studies identified two loci (MS8 and MSP1-B10) that could be used to discriminate between both CQ-susceptible phenotypes among P. vivax isolates in vitro. These preliminary data suggest that microsatellites may be used to identify and to monitor the spread of P. vivax-resistance around the world.     

地塞美松中间体的C1,4脱氢和11α-羟基化

地塞美松 (Ｄｅｘａｍｅｔｈａｓｏｎｅ)为高效肾上腺皮质激素药物 ,临床上广泛使用。开拓用梯可吉宁 (Ｔｉｇｏｇｅｎｉｎ)为起始原料生产从化学结构和合成技术上讲较为合理 ,而且适合于资源综合利用[1] 。在合成过程中 ,除了Ａ环需引入Ｃ1,2 和Ｃ4 ,5两个双键 (含Ｃ-3 羟基氧化 )外 ,还需用微生物法在Ｃ-11位引入羟基。国外常采用化学法脱氢 ,然后再用霉菌 11α 羟基化[2 ,3 ] 。本文报道用两类微生物菌种 ,节杆菌 (Ａｒｔｈｒｏｂａｃｔｅｒｓｐ .)ＡＸ86和绿僵菌 (Ｍｅｔａｒｈｉｚｉｕｍｓｐ .)Ｍ 88,混合转化一步完成脱氢和羟基化反应…     

A correlation between BCL-2 modifying factor,p53 and livin gene expressions in cancer colon patients

Accumulating evidence has revealed that livin gene and BCL-2 modifying factor (BMF) gene are closely associated with the initiation and progression of colon carcinoma by activating or suppressing multiple malignant processes. Those genes that can detect colon - cancer are a promising approach for cancer screening and diagnosis. This study aimed to evaluate correlation between livin, BMF and p53 genes expression in colon cancer tissues of patients included in the study, and their relationship with clinicopathological features and survival outcome in those patients. In this study, 50 pathologically diagnosed early cancer colon patients included and their tissue biopsy with 50 matched adjacent normal tissue, and 50 adenoma tissue specimens were analyzed for livin gene and BMF gene expressions using real time PCR. The relationship of those genes expressions with clinicopathological features, tumor markers, Time to Progression and overall survival for those patients were correlated in cancer colon group. In this study, there was a significant a reciprocal relationship between over expression of livin gene and down regulation of BMF and p53 genes in colon cancer cells. Livin mRNA was significantly higher, while BMF and p53 mRNA were significantly lower in colorectal cancer tissue compared to benign and normal colon tissue specimens (P < 0.001), however, this finding was absent between colon adenomas and normal mucosa. There was a significant association between up regulation of livin and down regulation of BMF and p53 expressions with more aggressive tumor (advanced TNM stage), rapid progression with metastasis and decreased overall survival in cancer colon patients, hence these genes can serve as significant prognostic markers of poor outcome in colon cancer patients. This work highlights the role of livin, BMF and p53 genes in colorectal tumorigenesis and the applicability of using those genes as a diagnostic and prognostic markers in patients with colon carcinoma and as a good target for cancer colon treatment in the future.     

Commitment to the First Cortical Reorganization During Conjugation in Stylonychia mytilus: An Argument for Homology with Cortical Development During Binary Fission

The asexual nature of the first cortical reorganization of conjugation in Stylonychia was analyzed by comparing the effect of amputation performed at different stages of early conjugation to that performed on vegetative cells at different stages of the cell cycle. Amputation of vegetative cells delineated a point of commitment to binary fission at 0.51–0.57 of the cell cycle. Cells amputated before this point were induced to undergo the regenerative mode of asexual development, but those amputated after this point continued with binary fission. In parallel, during conjugation a similar commitment was made around the time of formation of tight mating-pairs: early conjugants amputated around this time might undergo regeneration, and those operated on after this stage continued with the first cortical reorganization as in typical conjugants. The two mates of a pair might differ in their response to amputation, suggesting that the timing of commitment to the first cortical reorganization is not related to the events of conjugation, but rather is individually determined in the vegetative cycle of the cells before they pair up in mating. These observations provide support for the notion that the first cortical reorganization of conjugants is homologous to the asexual mode of cortical development in dividers, according to the theory of developmental heterochrony in the sexual reproduction of hypotrichs. The timing of commitment to the first cortical reorganization was found to temporally correlate with the entrance of the micronuclei into meiosis. Since the first cortical reorganization can proceed without the micronucleus, this raises the possibility that initiation of micronuclear meiosis is closely coupled with, and may be determined by, the commitment to the first cortical reorganization.     

Increased hexokinase activity, of either ectopic or endogenous origin, protects renal epithelial cells against acute oxidant-induced cell death.

Glucose (Glc) metabolism protects cells against oxidant injury. By virtue of their central position in both Glc uptake and utilization, hexokinases (HKs) are ideally suited to contribute to these effects. Compatible with this hypothesis, endogenous HK activity correlates inversely with injury susceptibility in individual renal cell types. We recently reported that ectopic HK expression mimics the anti-apoptotic effects of growth factors in cultured fibroblasts, but anti-apoptotic roles for HKs have not been examined in other cell types or in a cellular injury model. We therefore evaluated HK overexpression for the ability to mitigate acute oxidant-induced cell death in an established epithelial cell culture injury model. In parallel, we examined salutary heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) treatment for the ability to 1) increase endogenous HK activity and 2) mimic the protective effects of ectopic HK expression. Both HK overexpression and HB-EGF increased Glc-phosphorylating capacity and metabolism, and these changes were associated with markedly reduced susceptibility to acute oxidant-induced apoptosis. The uniform Glc dependence of these effects suggests an important adaptive role for Glc metabolism, and for HK activity in particular, in the promotion of epithelial cell survival. These findings also support the contention that HKs contribute to the protective effects of growth factors.     

Fractional diffusion-limited component of reactions catalyzed by acetylcholinesterase

The values of kcat/Km for the reactions of four substrates, p-nitrophenyl acetate (PNPA), propionyl-beta-methylthiocholine (PrMSCh), 3,3-dimethylbutyl thioacetate (DBTA), and acetylthiocholine (AcSCh), with acetylcholinesterase were determined as a function of increasing viscosity (eta rel) in sucrose-containing and in glycerol-containing buffers. Glycerol, or possibly some contaminant of it, was found to be a nonspecific inhibitor and sucrose a nonspecific activator of the enzyme as reflected in the dependence of kcat/Km values measured for PNPA and PrMSCh upon the concentration of these reagents. The rates of reactions of these two substrates, the first neutral and the second cationic, are chemically limited rather than diffusion limited, and they thus serve as quantitative controls or internal standards to monitor the effects of the viscosogens on the enzyme, which are not related to diffusion. The additional effect on kcat/Km over the controls observed for the rapidly reacting substrates AcSCh (cationic) and DBTA (neutral) serves as a measure of the extent to which these values of kcat/Km measure diffusion-controlled processes. The reaction rate of DBTA with the enzyme is 24% diffusion controlled as measured in glycerol-containing buffers and 16-20% as determined in sucrose-containing buffers, while that for AcSCh is 100% (in glycerol) and 24-40% (in sucrose) diffusion controlled.     

A pentapeptide from the laminin B1 chain mediates cell adhesion and binds the 67,000 laminin receptor

Laminin promotes epithelial cell adhesion in part through a site of nine amino acids CDPGYIGSR on the B1 chain. Using smaller synthetic peptides from this sequence as well as various peptides with amino acid substitutions, we find that the minimum sequence necessary for efficient cell adhesion as well as receptor binding is YIGSR. The deletion of tyrosine or the substitution of arginine in the peptides resulted in a significant loss of activity. The presence of an amide group on the terminal arginine of either peptide increases activity significantly. YIGSR is active in promoting the adhesion of a variety of epithelial cells; however, it is inactive with chondrocytes, fibroblasts, and osteoblasts.