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11.
The secondary metabolite 2,4,6-triphenylaniline (TPA) was isolated from an endophytic fungi Alternaria longipes strain VITN14G of mangrove plant Avicennia officinalis, that exhibited satisfactory in vitro antidiabetic activity for type 2 diabetes mellitus (T2DM). The TPA was encapsulated using nanoemulsion (NE) to overcome the problem of stability and permeability to increase its therapeutic applications. Response surface methodology (RSM) was used for the optimization of the variables given, such as hydrodynamic diameter, surface charge, and polydispersity index (PDI). TPA was encapsulated using an optimized ratio of olive oil and tween 80 (2:1) significantly affected the response variables including particle size (124.8 nm), ζ potential (−46.0 mV), and PDI (0.396), and the encapsulation efficiency was found to be 95.93%. The TPA-loaded NE after MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) analysis showed nontoxic effects on L929 normal cell lines (areolar and adipose subcutaneous connective tissue of Mus musculus) with a viable percentage of 92%. In vitro release study revealed the slow and sustained release of the TPA over 48 hrs from NE under the Fickian diffusion mechanism and followed the Higuchi model for release kinetics. Further, the percentage of α-glucosidase and α-amylase inhibition rate of TPA-loaded NE was found to be 78.5 and 43.42%, respectively. The present study, therefore, can aid in the development of a novel drug delivery system as a therapeutic approach to T2DM. 相似文献
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Rui Wang Srivathsan V. Ranganathan Phensinee Haruehanroengra Song Mao Matteo Scalabrin Daniele Fabris 《Journal of biomolecular structure & dynamics》2019,37(3):551-561
The facile construction of metal–DNA complexes using ‘Click’ reactions is reported here. A series of 2′-propargyl-modified DNA oligonucleotides were initially synthesized as structure scaffolds and were then modified through ‘Click’ reaction to incorporate a bipyridine ligand equipped with an azido group. These metal chelating ligands can be placed in the DNA context in site-specific fashion to provide versatile templates for binding various metal ions, which are exchangeable using a simple EDTA washing-and-filtration step. The constructed metal–DNA complexes were found to be thermally stable. Their structures were explored by solving a crystal structure of a propargyl-modified DNA duplex and installing the bipyridine ligands by molecular modeling and simulation. These metal–DNA complexes could have wide applications as novel organometallic catalysts, artificial ribonucleases, and potential metal delivery systems. 相似文献
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Carolyn M. Kelly Peter J. Zeiger Vinodh Narayanan Keri Ramsey Holger Sondermann 《The Journal of biological chemistry》2022,298(1)
Hereditary spastic paraplegia (HSP) comprises a heterogeneous group of neuropathies affecting upper motor neurons and causing progressive gait disorder. Mutations in the gene SPG3A/atlastin-1 (ATL1), encoding a dynamin superfamily member, which utilizes the energy from GTP hydrolysis for membrane tethering and fusion to promote the formation of a highly branched, smooth endoplasmic reticulum (ER), account for approximately 10% of all HSP cases. The continued discovery and characterization of novel disease mutations are crucial for our understanding of HSP pathogenesis and potential treatments. Here, we report a novel disease-causing, in-frame insertion in the ATL1 gene, leading to inclusion of an additional asparagine residue at position 417 (N417ins). This mutation correlates with complex, early-onset spastic quadriplegia affecting all four extremities, generalized dystonia, and a thinning of the corpus callosum. We show using limited proteolysis and FRET-based studies that this novel insertion affects a region in the protein central to intramolecular interactions and GTPase-driven conformational change, and that this insertion mutation is associated with an aberrant prehydrolysis state. While GTPase activity remains unaffected by the insertion, membrane tethering is increased, indicative of a gain-of-function disease mechanism uncommon for ATL1-associated pathologies. In conclusion, our results identify a novel insertion mutation with altered membrane tethering activity that is associated with spastic quadriplegia, potentially uncovering a broad spectrum of molecular mechanisms that may affect neuronal function. 相似文献
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Role of protein kinase C in the translational regulation of lipoprotein lipase in adipocytes 总被引:1,自引:0,他引:1
The hypertriglyceridemia of diabetes is accompanied by decreased lipoprotein lipase (LPL) activity in adipocytes. Although the mechanism for decreased LPL is not known, elevated glucose is known to increase diacylglycerol, which activates protein kinase C (PKC). To determine whether PKC is involved in the regulation of LPL, we studied the effect of 12-O-tetradecanoyl phorbol 13-acetate (TPA) on adipocytes. LPL activity was inhibited when TPA was added to cultures of 3T3-F442A and rat primary adipocytes. The inhibitory effect of TPA on LPL activity was observed after 6 h of treatment, and was observed at a concentration of 6 nM. 100 nM TPA yielded maximal (80%) inhibition of LPL. No stimulation of LPL occurred after short term addition of TPA to cultures. To determine whether TPA treatment of adipocytes decreased LPL synthesis, cells were labeled with [35S]methionine and LPL protein was immunoprecipitated. LPL synthetic rate decreased after 6 h of TPA treatment. Western blot analysis of cell lysates indicated a decrease in LPL mass after TPA treatment. Despite this decrease in LPL synthesis, there was no change in LPL mRNA in the TPA-treated cells. Long term treatment of cells with TPA is known to down-regulate PKC. To assess the involvement of the different PKC isoforms, Western blotting was performed. TPA treatment of 3T3-F442A adipocytes decreased PKC alpha, beta, delta, and epsilon isoforms, whereas PKC lambda, theta, zeta, micro, iota, and gamma remained unchanged or decreased minimally. To directly assess the effect of PKC inhibition, PKC inhibitors (calphostin C and staurosporine) were added to cultures. The PKC inhibitors inhibited LPL activity rapidly (within 60 min). Thus, activation of PKC did not increase LPL, but inhibition of PKC resulted in decreased LPL synthesis by inhibition of translation, indicating a constitutive role of PKC in LPL gene expression. 相似文献
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Di Gregorio GB Hensley L Lu T Ranganathan G Kern PA 《American journal of physiology. Endocrinology and metabolism》2004,287(1):E182-E187
Obesity-related insulin resistance may be caused by adipokines such as IL-6, which is known to be elevated with the insulin resistance syndrome. A previous study reported that IL-6 knockout mice (IL-6(-/-)) developed maturity onset obesity, with disturbed carbohydrate and lipid metabolism, and increased leptin levels. Because IL-6 is associated with insulin resistance, one might have expected IL-6(-/-) mice to be more insulin sensitive. We examined body weights of growing and older IL-6(-/-) mice and found them to be similar to wild-type (IL-6(+/+)) mice. Dual-energy X-ray absorptiometry analysis at 3 and 14 mo revealed no differences in body composition. There were no differences in fasting blood insulin and glucose or in triglycerides. To further characterize these mice, we fed 11-mo-old IL-6(-/-) and IL-6(+/+) mice a high- (HF)- or low-fat diet for 14 wk, followed by insulin (ITT) and glucose tolerance tests (GTT). An ITT showed insulin resistance in the HF animals but no difference due to genotype. In the GTT, IL-6(-/-) mice demonstrated elevated postinjection glucose levels by 60% compared with IL-6(+/+) but only in the HF group. Although IL-6(-/-) mice gained weight and white adipose tissue (WAT) with the HF diet, they gained less weight than the IL-6(+/+) mice. Total lipoprotein lipase activity in WAT, muscle, and postheparin plasma was unchanged in the IL-6 (-/-) mice compared with IL-6(+/+) mice. There were no differences in plasma leptin or TNF-alpha due to genotype. Plasma adiponectin was approximately 53% higher (71.7 +/- 14.1 microg/ml) in IL-6(-/-) mice than in IL-6(+/+) mice but only in the HF group. Thus these data show that IL-6(-/-) mice do not demonstrate obesity, fasting hyperglycemia, or abnormal lipid metabolism, although HF IL-6(-/-) mice demonstrate elevated glucose after a GTT. 相似文献
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Hensley LL Ranganathan G Wagner EM Wells BD Daniel JC Vu D Semenkovich CF Zechner R Kern PA 《The Journal of biological chemistry》2003,278(35):32702-32709
Lipoprotein lipase (LPL) is a key enzyme in lipoprotein and adipocyte metabolism. Defects in LPL can lead to hypertriglyceridemia and the subsequent development of atherosclerosis. The mechanisms of regulation of this enzyme are complex and may occur at multiple levels of gene expression. Because the 3'-untranslated region (UTR) is involved in LPL translational regulation, transgenic mice were generated with adipose tissue expression of an LPL construct either with or without the proximal 3'-UTR and driven by the aP2 promoter. Both transgenic mouse colonies were viable and expressed the transgene, resulting in a 2-fold increase in LPL activity in white adipose tissue. Neither mouse colony exhibited any obvious phenotype in terms of body weight, plasma lipids, glucose, and non-esterified fatty acid levels. In the mice expressing hLPL with an intact 3'-UTR, hLPL mRNA expression approximately paralleled hLPL activity. However in the mice without the proximal 3'-UTR, hLPL mRNA was low in the setting of large amounts of hLPL protein and LPL activity. In previous studies, the 3'-UTR of LPL was critical for the inhibitory effects of constitutively expressed hormones, such as thyroid hormone and catecholamines. Therefore, these data suggest that the absence of the 3'-UTR results in a translationally unrepressed LPL, resulting in a moderate overexpression of adipose LPL activity. 相似文献