An accelerated synthesis of dendrimers is presented by combining the thermal azide-alkyne cycloaddition (AAC) and azide substitution reactions. The strategy is among the most user-friendly, flexible, ...modular, and accelerated strategies for the synthesis of dendrimers. Despite AAC being an archetypal click reaction that proceeds with complete atom-economy and is amenable to a high chemical diversity, high temperatures and prolonged reaction times have limited its application in the synthesis of dendrimers. By combining the optimized AAC/azide substitution conditions, simplified workups/purifications, and a strict alignment to green chemistry principles, not only a G5 dendrimer with 96 terminal groups has been synthesized and characterized in less than 12 h, but also the newly formed triazol has been successfully used to promote the easy exploration of the dendritic chemical space, the peripheral decoration of dendrimers, and the straightforward adjustment of dendritic properties.
Optimized reaction conditions and a strict alignment to green chemistry principles allow the accelerated preparation of a G5 dendrimer in less than 12 h by combining the thermal azide-alkyne cycloaddition and azide substitution reactions.
The generation of dendrimers is a powerful tool in the control of the size and biodistribution of polyion complexes (PIC). Using a combinatorial screening of six dendrimers (18–243 terminal groups) ...and five oppositely charged PEGylated copolymers, a dendrimer‐to‐PIC hierarchical transfer of structural information was revealed with PIC diameters that increased from 80 to 500 nm on decreasing the dendrimer generation. This rise in size, which was also accompanied by a micelle‐to‐vesicle transition, is interpreted according to a cone‐ to rod‐shaped progression in the architecture of the unit PIC (uPIC). This precise size tuning enabled dendritic PICs to act as nanorulers for controlled biodistribution. Overall, a domino‐like control of the size and biological properties of PIC that is not attainable with linear polymers is feasible through dendrimer generation.
PIC and choose: The size and biodistribution of polyion complexes (PICs) can be hierarchically tuned with the generation of a dendrimer component in a way not attainable with linear polymers.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A multigram synthesis of the repeating unit of GATG (gallic acid-triethylene glycol) dendrimers is described through an efficient and cost-effective route. These conditions overcome major problems ...precluding scaling up and afford product in excellent overall yield and purity. Special attention has been paid in this process to green chemistry principles: atom economy, safety, and waste reduction. This scheme could be easily adapted for the preparation of similar dendritic systems.
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IJS, KILJ, NUK, PNG, UL, UM
Here, we evaluate how cationic gallic acid-triethylene glycol (GATG) dendrimers interact with bacteria and their potential to develop new antimicrobials. We demonstrate that GATG dendrimers ...functionalised with primary amines in their periphery can induce the formation of clusters in Vibrio harveyi, an opportunistic marine pathogen, in a generation dependent manner. Moreover, these cationic GATG dendrimers demonstrate an improved ability to induce cluster formation when compared to poly(N-3-(dimethylamino)propylmethacrylamide) p(DMAPMAm), a cationic linear polymer previously shown to cluster bacteria. Viability of the bacteria within the formed clusters and evaluation of quorum sensing controlled phenotypes (i.e. light production in V. harveyi) suggest that GATG dendrimers may be activating microbial responses by maintaining a high concentration of quorum sensing signals inside the clusters while increasing permeability of the microbial outer membranes. Thus, the reported GATG dendrimers constitute a valuable platform for the development of novel antimicrobial materials that can target microbial viability and/or virulence.
We evaluated whether genetic predisposition is sufficient to induce changes due to chronic high glucose (HG; 25 mmol/L) in the presence or absence of insulin (HGI; 10 μg/ml) on osteogenic ...differentiation and markers in bone‐marrow mesenchymal stem cells (BMSCs) from young Wistar (WBMSCs) and spontaneous hypertensive rats (SBMSCs) without hypertension. HG suppressed osteogenic differentiation in both the strains, observed by mineralization inhibition and decreased levels of the osteogenic markers Runx2, osterix, osteopontin, and bone sialoprotein, compared to osteogenic medium (OM) cells. In WBMSCs, the effects of HG were associated with the down regulation of ERK1/2 and up regulation of p38 activities; however, HGI did not revert the effects of HG on MAPK activities. Moreover, HG did not affect MAPK signaling in SBMSCs compared to that in OM. HGI increased mineralization in WBMSCs compared to that in OM, but not in SBMSCs. High expression of peroxisome proliferator‐activated receptor‐gamma and glucose transporter type 4 in OM could be related with the predisposition to adipogenic differentiation noted in SBMSCs and was confirmed by emergence of adipocyte‐like cells by HGI treatment. Downregulation of p38 and upregulation of JNK activities were observed in both BMSCs treated with HGI compared to those treated by HG. Ma (osmotic control) also suppressed osteogenic differentiation in both the strains. In conclusion, we demonstrated that SBMSCs from young spontaneous hypertensive rats, without hypertension but with genetic and epigenetic predisposition, exhibited decreased osteoblastic differentiation under HG and HGI did not revert the effects of HG in SBMSCs but increased adipogenic differentiation.
Our study demonstrated that bone‐marrow mesenchymal stem cells from young spontaneous hypertensive rats SBMSCs, without hypertension but with genetic and epigenetic predisposition, exhibited decreased osteoblastic differentiation under high glucose (25 mmol/L). Furthermore, high glucose (25 mmol/L) + insulin (10 μg/ml) did not revert the effects of high glucose (25 mmol/L) in SBMSCs but increased adipogenic differentiation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The generation of dendrimers is a powerful tool in the control of the size and biodistribution of polyion complexes (PIC). Using a combinatorial screening of six dendrimers (18–243 terminal groups) ...and five oppositely charged PEGylated copolymers, a dendrimer‐to‐PIC hierarchical transfer of structural information was revealed with PIC diameters that increased from 80 to 500 nm on decreasing the dendrimer generation. This rise in size, which was also accompanied by a micelle‐to‐vesicle transition, is interpreted according to a cone‐ to rod‐shaped progression in the architecture of the unit PIC (uPIC). This precise size tuning enabled dendritic PICs to act as nanorulers for controlled biodistribution. Overall, a domino‐like control of the size and biological properties of PIC that is not attainable with linear polymers is feasible through dendrimer generation.
Größe und Bioverteilung von Polyion‐Komplexen (PICs) können über die Generation einer Dendrimerkomponente vorgegeben werden. Mit linearen Polymeren ist ein solcher hierarchischer Ansatz nicht möglich.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Here, we evaluate how cationic gallic acid-triethylene glycol (GATG) dendrimers interact with bacteria and their potential to develop new antimicrobials. We demonstrate that GATG dendrimers ...functionalised with primary amines in their periphery can induce the formation of clusters in
Vibrio harveyi
, an opportunistic marine pathogen, in a generation dependent manner. Moreover, these cationic GATG dendrimers demonstrate an improved ability to induce cluster formation when compared to poly(
N
-3-(dimethylamino)propylmethacrylamide) p(DMAPMAm), a cationic linear polymer previously shown to cluster bacteria. Viability of the bacteria within the formed clusters and evaluation of quorum sensing controlled phenotypes (
i.e.
light production in
V. harveyi
) suggest that GATG dendrimers may be activating microbial responses by maintaining a high concentration of quorum sensing signals inside the clusters while increasing permeability of the microbial outer membranes. Thus, the reported GATG dendrimers constitute a valuable platform for the development of novel antimicrobial materials that can target microbial viability and/or virulence.
The potential of GATG dendrimers to underpin the development of novel antimicrobials targeting adhesion, signaling and/or membranes has been evaluated.
BACKGROUND Mitochondria are multitasking organelles involved in ATP synthesis, reactive oxygen species (ROS) production, calcium signalling and apoptosis; and mitochondrial defects are known to cause ...physiological dysfunction, including infertility. The goal of this review was to identify and discuss common themes in mitochondrial function related to mammalian reproduction. METHODS The scientific literature was searched for studies reporting on the several aspects of mitochondrial activity in mammalian testis, sperm, oocytes, early embryos and embryonic stem cells. RESULTS ATP synthesis and ROS production are the most discussed aspects of mitochondrial function. Metabolic shifts from mitochondria-produced ATP to glycolysis occur at several stages, notably during gametogenesis and early embryo development, either reflecting developmental switches or substrate availability. The exact role of sperm mitochondria is especially controversial. Mitochondria-generated ROS function in signalling but are mostly described when produced under pathological conditions. Mitochondria-based calcium signalling is primarily important in embryo activation and embryonic stem cell differentiation. Besides pathologically triggered apoptosis, mitochondria participate in apoptotic events related to the regulation of spermatogonial cell number, as well as gamete, embryo and embryonic stem cell quality. Interestingly, data from knock-out (KO) mice is not always straightforward in terms of expected phenotypes. Finally, recent data suggests that mitochondrial activity can modulate embryonic stem cell pluripotency as well as differentiation into distinct cellular fates. CONCLUSIONS Mitochondria-based events regulate different aspects of reproductive function, but these are not uniform throughout the several systems reviewed. Low mitochondrial activity seems a feature of ‘stemness’, being described in spermatogonia, early embryo, inner cell mass cells and embryonic stem cells.
Tuberculosis remains second only to HIV/AIDS as the leading cause of mortality worldwide due to a single infectious agent. Despite chemotherapy, the global tuberculosis epidemic has intensified ...because of HIV co-infection, the lack of an effective vaccine and the emergence of multi-drug-resistant bacteria. Alternative host-directed strategies could be exploited to improve treatment efficacy and outcome, contain drug-resistant strains and reduce disease severity and mortality. The innate inflammatory response elicited by Mycobacterium tuberculosis (Mtb) represents a logical host target. Here we demonstrate that interleukin-1 (IL-1) confers host resistance through the induction of eicosanoids that limit excessive type I interferon (IFN) production and foster bacterial containment. We further show that, in infected mice and patients, reduced IL-1 responses and/or excessive type I IFN induction are linked to an eicosanoid imbalance associated with disease exacerbation. Host-directed immunotherapy with clinically approved drugs that augment prostaglandin E2 levels in these settings prevented acute mortality of Mtb-infected mice. Thus, IL-1 and type I IFNs represent two major counter-regulatory classes of inflammatory cytokines that control the outcome of Mtb infection and are functionally linked via eicosanoids. Our findings establish proof of concept for host-directed treatment strategies that manipulate the host eicosanoid network and represent feasible alternatives to conventional chemotherapy.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Altered DNA methylation has been associated with various diseases.
We evaluated the association between levels of methylation in leukocyte DNA at long interspersed nuclear element 1 (LINE-1) and ...genetic and non-genetic characteristics of 892 control participants from the Spanish Bladder Cancer/EPICURO study.
We determined LINE-1 methylation levels by pyrosequencing. Individual data included demographics, smoking status, nutrient intake, toenail concentrations of 12 trace elements, xenobiotic metabolism gene variants, and 515 polymorphisms among 24 genes in the one-carbon metabolism pathway. To assess the association between LINE-1 methylation levels (percentage of methylated cytosines) and potential determinants, we estimated beta coefficients (βs) by robust linear regression.
Women had lower levels of LINE-1 methylation than men (β = -0.7, p = 0.02). Persons who smoked blond tobacco showed lower methylation than nonsmokers (β = -0.7, p = 0.03). Arsenic toenail concentration was inversely associated with LINE-1 methylation (β = -3.6, p = 0.003). By contrast, iron (β = 0.002, p = 0.009) and nickel (β = 0.02, p = 0.004) were positively associated with LINE-1 methylation. Single nucleotide polymorphisms (SNPs) in DNMT3A (rs7581217-per allele, β = 0.3, p = 0.002), TCN2 (rs9606756-GG, β = 1.9, p = 0.008; rs4820887-AA, β = 4.0, p = 4.8 × 10-7; rs9621049-TT, β = 4.2, p = 4.7 × 10-9), AS3MT (rs7085104-GG, β = 0.7, p = 0.001), SLC19A1 (rs914238, TC vs. TT: β = 0.5 and CC vs. TT: β = -0.3, global p = 0.0007) and MTHFS (rs1380642, CT vs. CC: β = 0.3 and TT vs. CC; β = -0.8, global p = 0.05) were associated with LINE-1 methylation.
We identified several characteristics, environmental factors, and common genetic variants that predicted DNA methylation among study participants.
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CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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