Deposition of doxorubicin in rats following administration of three newly synthesized doxorubicin conjugates.
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ABSTRACT:
SUBMITTER: Huan M
PROVIDER: S-EPMC3870082 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
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Project description:Inflammation in muscle induces the synthesis of mediators that can impair protein synthesis and enhance proteolysis, and when sustained lead to muscle atrophy. Furthermore, muscle-derived mediators that are secreted may participate in disrupting the function of other peripheral organs. Selective identification of newly synthesized proteins can provide insight on biological processes that depend on the continued synthesis of specific proteins to maintain homeostasis as well as those proteins that are up- or down-regulated in response to inflammation. We used puromycin-associated nascent chain proteomics (PUNCH-P) to characterize new protein synthesis in C2C12 myotubes and changes resulting from their exposure to the inflammatory mediators lipopolysaccharide (LPS) and interferon (IFN)-γ for either a short (4 h) or prolonged (16 h) time period. We identified sequences of nascent polypeptide chains belonging to a total of 1523 proteins and report their detection from three independent samples of each condition at each time point. The identified nascent proteins correspond to approximately 15% of presently known proteins in C2C12 myotubes and are enriched in specific cellular components and pathways. A subset of these proteins was identified only in treated samples and has functional characteristics consistent with the synthesis of specific new proteins in response to LPS/IFNγ. Thus, the identification of proteins from their nascent polypeptide chains provides a resource to analyze the role of new synthesis of proteins in both protein homeostasis and in proteome responses to stimuli in C2C12 myotubes. Our results reveal a profile of actively translating proteins for specific cellular components and biological processes in normal C2C12 myotubes and a different enrichment of proteins in response to LPS/IFNγ. Collectively, our data disclose a highly interconnected network that integrates the regulation of cellular proteostasis and reveal a diverse immune response to inflammation in muscle which may underlie the concomitantly observed atrophy and be important in inter-organ communication.
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Project description:BackgroundCannabigerol (CBG), a non-psychotropic phytocannabinoid found in Cannabis sativa plants, has been the focus of recent studies due to its potential therapeutic properties. We proposed that by focusing on sphingolipid metabolism, which plays a critical role in insulin signaling and the development of insulin resistance, CBG may provide a novel therapeutic approach for metabolic disorders, particularly insulin resistance.MethodsIn a rat model of insulin resistance induced by a high-fat, high-sucrose diet (HFHS), we aimed to elucidate the effect of intragastrically administered CBG on hepatic sphingolipid deposition and metabolism. Moreover, we also elucidated the expression of sphingolipid transporters and changes in the sphingolipid concentration in the plasma.ResultsThe results, surprisingly, showed a lack of changes in de novo ceramide synthesis pathway enzymes and significant enhancement in the expression of enzymes involved in ceramide catabolism, which was confirmed by changes in hepatic sphingomyelin, sphinganine, sphingosine-1-phosphate, and sphinganine-1-phosphate concentrations.ConclusionsThe results suggest that CBG treatment may modulate sphingolipid metabolism in the liver and plasma, potentially protecting the liver against the development of metabolic disorders such as insulin resistance.
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2024-03-14 | GSE261145 | GEO
Project description:Measuring proteome response to perturbations is critical for understanding the underlying mechanisms involved. Traditional quantitative proteomic methods are limited by the large numbers of proteins in the proteome and the mass spectrometer's dynamic range. A previous method uses the biorthogonal reagent azidohomoalanine (AHA), a methionine analog, for labeling, enrichment and detection of newly synthesized proteins (NSPs). Newly synthesized AHA proteins can be coupled to biotin via CuAAC-mediated click chemistry and enriched using avidin-based affinity purification. The combination of AHA-mediated NSP labeling with metabolic stable isotope labeling allows quantitation of low-abundant, newly secreted proteins by mass spectrometry (MS). However, the resulting multiplicity of labeling complicates NSP analysis. We developed a new NSP quantification strategy, called HILAQ (heavy isotope-labeled azidohomoalanine quantification), that uses a heavy isotope-labeled AHA molecule to enable NSP labeling, enrichment, identification and quantification. In addition, the AHA-peptide enrichment used in HILAQ improves both the identification and quantification of NSPs over AHA-protein enrichment. Here, we provide a description of the HILAQ method that includes procedures for (i) pulse-labeling and harvesting NSPs; (ii) addition of biotin by click reaction; (iii) protein precipitation; (iv) protein digestion; (v) enrichment of AHA-biotin peptides by NeutrAvidin beads and four-step elution; (vi) MS analysis; and (vii) data analysis for the identification and quantification of NSPs by ProLuCID and pQuant. We demonstrate our HILAQ approach by identifying NSPs from cell cultures, but we anticipate that it can be adapted for applications in animal models. The whole protocol takes ~6 d to complete.
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Project description:Light-mediated polymer degradation has attracted considerable attention in various applications, including photo-patterning, tissue engineering and photo-triggered drug delivery. In this study, we report the synthesis and characterization of a new, linear, main-chain photo- and acid-degradable copolymer based on acylhydrazone linkages. The polymer was synthesized via a step-growth copolymerization of adipic acid dihydrazide with a bifunctional poly(ethylene glycol) bearing benzaldehyde end-groups, under mild acidic conditions, to afford a hydrophilic PEG-alt-adipic acid (PEG-alt-AA) alternating copolymer. The synthesized polymer was characterized by size exclusion chromatography, proton nuclear magnetic resonance and attenuated total reflection-Fourier transform infrared spectroscopies. The main-chain photo- and acid-induced degradation of the copolymer in dimethylsulfoxide and water, respectively, was verified by UV-vis spectroscopy at light intensities as low as 0.1 mW cm-2 at λ = 254 nm. Next, a model anticancer drug, doxorubicin (DOX), was chemically linked to the polymer chain end(s) via acylhydrazone bond(s), resulting in amphiphilic PEG-alt-adipic acid-DOX (PEG-alt-AA-DOX) polymer-drug conjugates. The conjugates were self-assembled in water to form spherical nanoparticles, as evidenced by scanning and transmission electron microscopies. The irradiation of the self-assembled PEG-alt-AA-DOX conjugates with UV light and the decrease of the solution pH resulted in the disruption of the assemblies due to the photolysis and acidolysis of the acylhydrazone bonds, and the release of the therapeutic cargo.
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Project description:Widespread application of carbendazim (CBZ) is a major environmental impact because of its residues that caused multi-organ dysfunction. Recently, Chitosan nanoparticles (CS-NPs) are extensively used as nanocarriers due to their non-toxic and biodegradable nature. Therefore, the current study aimed to investigate the possible mechanistic pathway of modified CS-NPs to reduce the hepatic and nephrotoxicity of CBZ in rats. CS-NPs were synthesized by the ionic gelation method by using ascorbic acid instead of acetic acid to increase its antioxidant efficiency. Twenty-adult male Wistar rats were grouped (n = 5) as follows: Group (1) negative control, group (2) received CS-NPs, group (3) received CBZ, and group (4) co-administered CS-NPs with CBZ. Rats received the aforementioned materials daily by oral gavage for 28 days and weighed weekly. The results revealed that CBZ receiving group showed severe histopathological alterations in the liver and kidney sections including cellular necrosis and interstitial inflammation confirmed by immunostaining and showed marked immunopositivity of iNOS and caspase-3 protein. There were marked elevations in the serum levels of ALT, AST, urea, and creatinine with a significant increase in MDA levels and decrease in TAC levels. Upregulation of the Keap1 gene and down-regulation of Nrf2 and HO-1 genes were also observed. Co-treatment of rats by CS-NPs with CBZ markedly improved all the above-mentioned toxicological parameters and return liver and kidney tissues to normal histological architecture. We concluded that CBZ caused hepatorenal toxicity via oxidative stress and the Nrf2/HO-1 pathway and CS-NPs could reduce CBZ toxicity via their antioxidant, anti-apoptotic, and anti-inflammatory effects.
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Project description:Rodent models of human disease can be valuable for understanding the mechanisms of a disease and for identifying novel therapies. However, it is critical that these models be vetted prior to committing resources to developing novel therapeutics. Failure to confirm the model can lead to significant losses in time and resources. One model used for migraine headache is to administer nitroglycerin to rodents. Nitroglycerin is known to produce migraine-like pain in humans and is presumed to do the same in rodents. It is not known, however, if the mechanism for nitroglycerin headaches involves the same pathological processes as migraine. In the absence of known mechanisms, it becomes imperative that the model not only translates into successful clinical trials but also successfully reverse translates by demonstrating efficacy of current therapeutics. In this study female rats were given nitroglycerin and nociception was evaluated in OPADs. Estrous was not monitored. Based on the ED50 of nitroglycerin a dose of 10 mg/kg was used for experiments. Sumatriptan, caffeine, buprenorphine and morphine were administered to evaluate the reverse translatability of the model. We found that nitroglycerin did not produce mechanical allodynia in the face of the rats, which is reported to be a consequence of migraine in humans. Nitroglycerin reduced the animals' participation in the assay. The reduced activity was verified using an assay to measure exploratory behavior. Furthermore, the effects of nitroglycerin were not reversed or prevented by agents that are effective acute therapies for migraine. Two interesting findings from this study, however, were that morphine and nitroglycerin interact to increase the rats' tolerance of mechanical stimuli on their faces, and they work in concert to slow down the central motor pattern generator for licking on the reward bottle. These interactions suggest that nitroglycerin generated nitric oxide and mu opioid receptors interact with the same neuronal circuits in an additive manner. The interaction of nitroglycerin and morphine on sensory and motor circuits deserves additional examination. In conclusion, based on the results of this study the use of nitroglycerin at these doses in naïve female rats is not recommended as a model for migraine headaches.
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Project description:ObjectivesBecause of its multifaceted cardioprotective effects, remote ischemic pre-conditioning (RIPC) was examined as a strategy to attenuate doxorubicin (DOX) cardiotoxicity.BackgroundThe use of DOX is limited by dose-dependent cardiotoxicity and heart failure. Oxidative stress, mitochondrial dysfunction, inflammation, and autophagy modulation have been proposed as mediators of DOX cardiotoxicity.MethodsAfter baseline echocardiography, adult male CD1 mice were randomized to either sham or RIPC protocol (3 cycles of 5 min femoral artery occlusion followed by 5 min reperfusion) 1 h before receiving DOX (20 mg/kg, intraperitoneal). The mice were observed primarily for survival over 85 days (86 mice). An additional cohort of 50 mice was randomized to either sham or RIPC 1 h before DOX treatment and was followed for 25 days, at which time cardiac fibrosis, apoptosis, and mitochondrial oxidative phosphorylation were assessed, as well as the expression profiles of apoptosis and autophagy markers.ResultsSurvival was significantly improved in the RIPC cohort compared with the sham cohort (p = 0.007). DOX-induced cardiac fibrosis and apoptosis were significantly attenuated with RIPC compared with sham (p < 0.05 and p < 0.001, respectively). Although no mitochondrial dysfunction was detected at 25 days, there was a significant increase in autophagy markers with DOX that was attenuated with RIPC. Moreover, DOX caused a 49% decline in cardiac BCL2/BAX expression, which was restored with RIPC (p < 0.05 vs. DOX). DOX also resulted in a 17% reduction in left ventricular mass at 25 days, which was prevented with RIPC (p < 0.01), despite the lack of significant changes in left ventricular ejection fraction.ConclusionsOur preclinical results suggested that RIPC before DOX administration might be a promising approach for attenuating DOX cardiotoxicity.
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Project description:Plants synthesize new ribosomal proteins and recycle others in cold-acclimated ribosomes and these in turn synthesize a differential proteome in barley root meristems.
2024-11-16 | PXD032923 | Pride