An amphiphilic dendrimer bearing a hydrophobic alkyl chain and hydrophilic poly(amidoamine) dendrons is able to combine the advantageous features of lipid and dendrimer vectors to deliver a heat shock protein 27 siRNA and produce potent gene silencing and anticancer activity in vitro and in vivo in a prostate cancer model. This dendrimer can be used alternatively for treating various diseases.
The preparation of chloride (1(n)) and bromide (2(n)) derivatives of 1-methyl-3-[3,4-bis(alkoxy)benzyl]-4H-imidazolium with n = 6, 12, 16, 18 is described. The two series of salts possess a rich thermotropic mesomorphism, chain-length dependent. Thus, a lamellar smectic A phase, a bicontinuous cubic Ia3d phase, and a columnar hexagonal liquid crystalline mesophase are induced as a function of increasing chain length. The mesomorphic properties were studied by polarizing optical microscopy, differential scanning calorimetry, and X-ray diffraction, and with the support of dilatometry and molecular dynamics, models for the various supramolecular arrangements of the salts are proposed. Such cationic amphiphiles were expected to be candidate molecules to design a new delivery reagent for nucleic acid transfection, particularly for short interfering RNA (siRNA). The use of an RNA interference mechanism, by introduction into cells by transfection of chemically synthesized siRNAs, is a powerful method for gene silencing studies. To exploit the potential of these amphilic imidazolium salts, these molecules were formulated with cohelper lipids and tested for their efficacy to deliver active siRNAs. Our results show high transfection efficacy of our formulated compounds and high silencing efficiency with more than 80% inhibition of the targeted gene at 10 nM siRNA concentration. Taken together our results show the potency of amphiphilic imidazolium salts as a new generation of transfection reagents for RNA interference.
The biological mechanisms of tooth movement result from the cellular responses of connective tissues to exogenous mechanical forces. Among these responses, the degradation of the extracellular matrix takes place, but the identification of the molecular basis as well as the components implicated in this degradation are poorly understood. To contribute to this identification, we subjected human fibroblasts obtained from the periodontal ligament (PDLs) and from the gingiva (HGFs) to a continuous stretch to quantify the mRNAs encoding for various metalloproteinases (MMPs), their tissue inhibitors (TIMPs), and alpha and beta integrin subunits. Both cell lines reacted by inducing the expression of the mRNAs encoding for MMP-1, MMP-2, TIMP-1, and TIMP-2, while other mRNAs did not vary (MT1-MMP, TIMP-3) or were not expressed (MMP-9). PDLs expressed selectively the mRNAs encoding for alpha4 and alphav, with no difference measurable under stretching, while the mRNAs encoding for alpha6 and beta1 were increased and the one encoding for alpha5 was decreased. HGFs increased the mRNAs encoding for alpha2, alpha6, beta1, and beta3 and decreased the one encoding for alpha3. Analysis of our data indicated that stretched HGFs and PDLs induced the same pattern of mRNAs encoding for MMPs and TIMPs but differed for those encoding various integrin subunits, known to act as protein receptors in mechanotransduction.
Our results did not reveal significant differences in the expression of mRNAs encoding for the MMPs between healthy and periodontitis-affected patients, reflecting the great heterogeneity in the periodontal status of individuals. However, they indicate that gingival fibroblasts are an active source of MMP-2 production in response to a periopathogen.
M-twist is the murine homolog of the Drosophila twist gene which is a zygotic target for maternal genes that establish embryonic dorso-ventral polarity and is necessary for mesoderm formation. We recently showed that before gastrulation, M-twist transcripts are detected in morulae and blastocysts, then in extra-embryonic tissues of early implanted mouse embryos before the onset of gastrulation, and we suggested that M-twist might be involved in embryonic polarity (Stoetzel et al., submitted). Here, using in situ hybridization on whole mount embryos, we present the expression pattern of M-twist from primitive streak stage up to 10.5 days p.c. In implanted embryos, M-twist is first expressed in extra-embryonic tissues, then in embryo proper around egg cylinder stage within some embryonic ectodermal cells of the primitive streak. Slightly later, scattered cells within the amniotic cavity apparently detached from the primitive streak also express the gene. Then, M-twist transcripts accumulate in head mesenchyme, the first aortic arches, somites and lateral mesoderm and, as development proceeds, successively the second, third and fourth branchial arches, the anterior limb buds and, finally, the posterior limb buds. Thus M-twist expression in implanted embryos occurs first along a dorso-ventral gradient pattern until the headfold stage, then it is gradually observed along the rostro-caudal axis of the embryos as development procedes in the mesodermal cell layer and in neural crest cell derivatives. In addition, we show the existence of some previously undescribed subsets of scattered cells that express M-twist and thus might participate in murine embryo development.
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