Follicular dendritic cells (FDC) are involved in the presentation of native Ags to B cells during the secondary immune response. Some authors consider FDC to be hemopoietic cells, whereas others believe them to be mesenchymal cells. The low proportion of FDC in the lymphoid follicle, together with technical difficulties in their isolation, make these cells difficult to study. We show that Fibroblast Medium can be used successfully to isolate and maintain FDC lines. In this culture medium, we obtained 18 FDC lines from human tonsils, which proliferated for as long as 18 wk and showed a stable Ag phenotype as detected by flow cytometry and RT-PCR. FDC lines were CD45-negative and expressed Ags associated to FDC (CD21, CD23, CD35, CD40, CD73, BAFF, ICAM-1, and VCAM-1) and Ags specific for FDC (DRC-1, CNA.42, and HJ2). These cell lines were also able to bind B cells and secrete CXCL13, functional activities characteristic of FDC. Nevertheless, the additional expression of STRO-1, together with CD10, CD13, CD29, CD34, CD63, CD73, CD90, ICAM-1, VCAM-1, HLA-DR, alkaline phosphatase, and α-smooth muscle actin (α-SM actin) indicated that FDC are closely related to bone marrow stromal cell progenitors. The expression of α-SM actin also relates FDC with myofibroblasts. Like myofibroblasts, FDC lines expressed stress fibers containing α-SM actin and were able to contract collagen gels under the effect of TGFβ1 and platelet-derived growth factor. These findings suggest that FDC are a specialized form of myofibroblast and derive from bone marrow stromal cell progenitors.

Decidual stromal cells (DSC) are the main cellular component of the human decidua, but thus far their ascription to a given cell lineage is uncertain. In previous studies, these cells have been isolated and maintained in culture, and their antigen phenotype has been analysed to determine their affiliation. However, the presence in the culture medium of high proportions of fetal calf serum (FCS) may inhibit the expression of some surface antigens. In the present study, we show by flow cytometry that CD34 is rapidly down-regulated in human DSC cultured in RPMI 1640 with 20% FCS. For this reason, we used fibroblast medium, which contains only a small proportion (2%) of FCS, to isolate and culture these cells. Under these conditions DSC exhibited a stable antigen phenotype highly similar to that of these cells in vivo. Flow cytometry results confirmed that DSC cultured in fibroblast medium expressed CD34 protein, and reverse transcription-polymerase chain reaction findings showed that they have CD34 mRNA. Decidual stromal cells were also positive for STRO-1, an antigen that identifies stromal precursors of the bone marrow which also expresses CD34. The expression of CD10, CD13, alkaline phosphatase and alpha-smooth muscle actin by DSC, and the absence of expression of CD14 and CD45, further confirmed their relationship with the stromal precursors.

The issue of drug chirality is now a major theme in the design and development of new drugs, underpinned by a new understanding of the role of molecular recognition in many pharmacologically relevant events. In general, three methods are utilized for the production of a chiral drug: the chiral pool, separation of racemates, and asymmetric synthesis. Although the use of chiral drugs predates modern medicine, only since the 1980's has there been a significant increase in the development of chiral pharmaceutical drugs. An important commercial reason is that as patents on racemic drugs expire, pharmaceutical companies have the opportunity to extend patent coverage through development of the chiral switch enantiomers with desired bioactivity. Stimulated by the new policy statements issued by the regulatory agencies, the pharmaceutical industry has systematically begun to develop chiral drugs in enantiometrically enriched pure forms. This new trend has caused a tremendous change in the industrial small- and large-scale production to enantiomerically pure drugs, leading to the revisiting and updating of old technologies, and to the development of new methodologies of their large-scale preparation (as the use of stereoselective syntheses and biocatalyzed reactions). The final decision whether a given chiral drug will be marketed in an enantiomerically pure form, or as a racemic mixture of both enantiomers, will be made weighing all the medical, financial and social proficiencies of one or other form. The kinetic, pharmacological and toxicological properties of individual enantiomers need to be characterized, independently of a final decision.

We previously demonstrated that human decidual stromal cells (DSC), the main cellular component of the decidua, are similar in antigen phenotype and structure to myofibroblasts, cells with contractile activity. In this work we isolated and maintained DSC in fibroblast medium, in which these cells show a stable phenotype similar to that of DSC in vivo. Flow cytometric observations showed that most DSC expressed alpha-smooth muscle (alpha-SM) actin, an intermediate filament that is considered a marker of myofibroblasts and is responsible for the contractile activity of these cells. alpha-SM actin mRNA was detected by RT-PCR in these cells. The contractile activity of DSC was determined by the gel contraction assay; we found that TGF beta 1 and platelet-derived-growth factor, cytokines that are known to be inducers of myofibroblast contractility, also induced contractility of DSC. IL-2, a Th1 cytokine-related with spontaneous abortion, also activated DSC contractility. Our results confirmed that DSC are phenotypically and functionally related with myofibroblast.

IL-10 relaxes DSC by reducing the incorporation of alpha-SM actin into their stress fibers. This relaxing activity may be of relevance for the maintenance of pregnancy.

Herein we report the design, synthesis, and anticancer activity of a series of substituted (R,S)-9-[2- or 3-(3,4-dihydro-2H-1,5-benzoxathiepine-3-yloxy)alkyl]-9H-purines. Derivatives with propylenoxy-linked 2',6'-dichloro- and 6'-bromopurines are more active than their respective ethylenoxy-linked purine conjugates. On the other hand, the compound with a propylenoxy-linked 6'-chloropurine is nearly equipotent to the corresponding ethylenoxy-linked conjugate. Our results show that bromo- and chloropurine-conjugated benzoxathiepines containing a propylenoxy linker are able to inhibit PI3 kinase (PI3K) phosphorylation in MCF-7 breast cancer cells, indicating that the activation of eIF2α, together with inhibition of the PI3K pathway, is the mechanism of action by which these compounds effect their antitumor activity in the MCF-7 cell line; apoptosis was induced in a p53-independent manner.

The 2,3-dihydro-1,4-benzodioxin ring system is present in a large number of structures of therapeutic agents possessing important biological activities. Some of them are antihypertensive agents. Others are involved in nervous breakdown and schizophrenia or represent an attractive therapeutic target for the treatment of glaucoma. The 2,3-dihydro-1,4-benzodioxin core has also been developed for the synthesis of inhibitors of 5-lipoxygenase and accordingly, these 2,3-dihydro-1,4-benzodioxins are useful for the treatment of inflammatory diseases such as asthma and arthritis. The synthesis and reactivity of several bioisosteres of the non-aromatic ring will be discussed. The occurrence of the 2,3-dihydro-1,4-benzodioxin structure in various naturally abundant compounds is also known. The total synthesis of angustureine (a novel 1,2,3,4-tetrahydroquinoline alkaloid with a n-pentyl side chain at position 2) will be presented. The bioisosteric replacement of benzene by pyridine in compounds containing the 2-substituted-2,3-dihydro-1,4-benzodioxin core has yielded derivatives of biological interest in diverse therapeutic areas such as central nervous system and cardiovascular diseases. These promising results have prompted interest in the area of 1,4-dioxino-[2,3-b]pyridine analogues. Several modifications on both the aromatic and the non-aromatic rings will be reviewed, including several transformations of the new heterocycles, such as the Smiles rearrangement. Moreover, the enantiomers of 2-and 3-hydroxymethyl-2,3-dihydro-1,4-dioxino-[2,3-b]pyridines, important chiral building blocks for the preparation of several biologically active compounds, have been synthesized. We have made an attempt to take into account the largest possible number of original papers, including our research and others. Publications of the last eleven years are included in this review.

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