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111.
Dasgupta I Tanifum EA Srivastava M Phatak SS Cavasotto CN Analoui M Annapragada A 《PloS one》2012,7(1):e29585
Boronic acids, known to bind diols, were screened to identify non-inflammatory cross-linkers for the preparation of glucose sensitive and insulin releasing agglomerates of liposomes (Agglomerated Vesicle Technology-AVT). This was done in order to select a suitable replacement for the previously used cross-linker, ConcanavalinA (ConA), a lectin known to have both toxic and inflammatory effects in vivo. Lead-compounds were selected from screens that involved testing for inflammatory potential, cytotoxicity and glucose-binding. These were then conjugated to insulin-encapsulating nanoparticles and agglomerated via sugar-boronate ester linkages to form AVTs. In vitro, the particles demonstrated triggered release of insulin upon exposure to physiologically relevant concentrations of glucose (10 mmoles/L-40 mmoles/L). The agglomerates were also shown to be responsive to multiple spikes in glucose levels over several hours, releasing insulin at a rate defined by the concentration of the glucose trigger. 相似文献
112.
Angiogenesis is an important step in the complex biological and molecular events leading to successful healing of dermal wounds. Among the different cellular effectors of wound angiogenesis, the role of mesenchymal stem cells (MSCs) is of current interest due to their transdifferentiation and proangiogenic potentials. Skin is richly innervated by sympathetic nerves which secrete dopamine (DA) and we have recently shown that concentration of DA present in synaptic cleft can significantly inhibit wound tissue neovascularization. As recent reports indicate that MSCs by mobilizing into wound bed play an important role in promoting wound angiogenesis, we therefore investigated the effect of DA on the migration of MSCs in wound tissues. DA acted through its D(2) receptors present in the MSCs to inhibit their mobilization to the wound beds by suppressing Akt phosphorylation and actin polymerization. In contrast, this inhibitory effect of DA was reversed after treatment with specific DA D(2) receptor antagonist. Increased mobilization of MSCs was demonstrated in the wound site following blockade of DA D(2) receptor mediated actions, and this in turn was associated with significantly more angiogenesis in wound tissues. This study is of translational value and indicates use of DA D(2) receptor antagonists to stimulate mobilization of these stem cells for faster regeneration of damaged tissues. 相似文献
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Phenotypic heterogeneity in an isogenic, microbial population enables a subset of the population to persist under stress. In mycobacteria, stresses like nutrient and oxygen deprivation activate the stress response pathway involving the two-component system MprAB and the sigma factor, SigE. SigE in turn activates the expression of the stringent response regulator, rel. The enzyme polyphosphate kinase 1 (PPK1) regulates this pathway by synthesizing polyphosphate required for the activation of MprB. The precise manner in which only a subpopulation of bacterial cells develops persistence, remains unknown. Rel is required for mycobacterial persistence. Here we show that the distribution of rel expression levels in a growing population of mycobacteria is bimodal with two distinct peaks corresponding to low (L) and high (H) expression states, and further establish that a positive feedback loop involving the mprAB operon along with stochastic gene expression are responsible for the phenotypic heterogeneity. Combining single cell analysis by flow cytometry with theoretical modeling, we observe that during growth, noise-driven transitions take a subpopulation of cells from the L to the H state within a "window of opportunity" in time preceding the stationary phase. It is these cells which adapt to nutrient depletion in the stationary phase via the stringent response. We find evidence of hysteresis in the expression of rel in response to changing concentrations of PPK1. Hysteresis promotes robustness in the maintenance of the induced state. Our results provide, for the first time, evidence that bistability and stochastic gene expression could be important for the development of "heterogeneity with an advantage" in mycobacteria and suggest strategies for tackling tuberculosis like targeting transitions from the low to the high rel expression state. 相似文献
118.
M. Dasgupta M. R. Sahoo P. C. Kole A. Mukherjee 《Plant Cell, Tissue and Organ Culture》2008,94(2):161-170
Fifteen genotypes of sweet potato were evaluated for salinity stress tolerance under in vitro NaCl mediated salinity stress
conditions (MS, MS + 0.5% and MS + 1.0% NaCl). The growth parameters such as number of leaves, number of shoots, number of
roots, length of plantlets and length of roots decreased significantly among the genotypes with increase in level of salinity.
Of the 15 genotypes tested, six genotypes (108X1, 90/606, 90/696, CIP 8, S-30X15 and SP-61) were unable to sprout even at
0.5% NaCl and were characterized as susceptible to salt stress, three genotypes (CIP 6, 90/774 and CIP 3) which could tolerate
0.5% NaCl as moderately tolerant and six genotypes (CIP 12, CIP 13, JO 14, JP 13, SB-198/115 and Gouri) as tolerant to salinity
at 1.0% NaCl. Amongst the six genotypes showing tolerance to 1.0% NaCl, the exotic genotypes––JP 13, CIP 12 and indigenous
one SB-198/115 continued to exhibit significant higher values for growth parameters over the susceptible one. Based on the
performance under NaCl mediated salinity stress (1.0%), the pattern of salinity tolerance in the genotypes through shoot apex
culture was JP 13 > SB-198/115 > JO 14 > Gouri > CIP 12 > CIP 13. The effect of salt stress on the activity of antioxidative
enzymes was studied in leaves of 8-week-old plantlets of those six genotypes, which responded at higher NaCl stress along
with a susceptible genotype 90/606. In leaves of salt stressed plants, superoxide dismutase (SOD), guaiacol peroxidase (GPX)
and catalase (CAT) activities increased when compared with the stress free control. The increase was more pronounced in the
tolerant genotypes than that in the susceptible one. These results indicate that oxidative stress may play an important role
in salt stressed sweet potato plants and that the greater protection of tolerant plants from salt induced oxidative damage
results, at least in part, through the increase in the activity of antioxidant enzymes. 相似文献
119.
Kaul DK Zhang X Dasgupta T Fabry ME 《American journal of physiology. Heart and circulatory physiology》2008,295(1):H39-H47
In sickle cell disease, nitric oxide (NO) depletion by cell-free plasma hemoglobin and/or oxygen radicals is associated with arginine deficiency, impaired NO bioavailability, and chronic oxidative stress. In transgenic-knockout sickle (BERK) mice that express exclusively human alpha- and beta(S)-globins, reduced NO bioavailability is associated with induction of non-NO vasodilator enzyme, cyclooxygenase (COX)-2, and impaired NO-mediated vascular reactivity. We hypothesized that enhanced NO bioavailability in sickle mice will abate activity of non-NO vasodilators, improve vascular reactivity, decrease hemolysis, and reduce oxidative stress. Arginine treatment of BERK mice (5% arginine in mouse chow for 15 days) significantly reduced expression of non-NO vasodilators COX-2 and heme oxygenase-1. The decreased COX-2 expression resulted in reduced prostaglandin E(2) (PGE(2)) levels. The reduced expression of non-NO vasodilators was associated with significantly decreased arteriolar dilation and markedly improved NO-mediated vascular reactivity. Arginine markedly decreased hemolysis and oxidative stress and enhanced NO bioavailability. Importantly, arteriolar diameter response to a NO donor (sodium nitroprusside) was strongly correlated with hemolytic rate (and nitrotyrosine formation), suggesting that the improved microvascular function was a response to reduced hemolysis. These results provide a strong rationale for therapeutic use of arginine in sickle cell disease and other hemolytic diseases. 相似文献
120.
Kreutter KD Lu T Lee L Giardino EC Patel S Huang H Xu G Fitzgerald M Haertlein BJ Mohan V Crysler C Eisennagel S Dasgupta M McMillan M Spurlino JC Huebert ND Maryanoff BE Tomczuk BE Damiano BP Player MR 《Bioorganic & medicinal chemistry letters》2008,18(9):2865-2870
2-Cyano-6-fluorophenylacetamide was explored as a novel P2 scaffold in the design of thrombin inhibitors. Optimization around this structural motif culminated in 14, which is a potent thrombin inhibitor (Ki = 1.2 nM) that exhibits robust efficacy in canine anticoagulation and thrombosis models upon oral administration. 相似文献