scholarly journals Dissecting the metabolic pathways controlling platelet survival in vivo: are our platelets what they eat?

Transfusion ◽  
2016 ◽  
Vol 56 (8) ◽  
pp. 1928-1931
Author(s):  
Shailaja Hegde ◽  
Jose A. Cancelas
Keyword(s):  
Metabolic Pathways ◽  
Platelet Survival

scholarly journals Integrated multi-omics analysis of RB-loss identifies widespread cellular programming and synthetic weaknesses

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Swetha Rajasekaran ◽  
Jalal Siddiqui ◽  
Jessica Rakijas ◽  
Brandon Nicolay ◽  
Chenyu Lin ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Human Cells ◽  
Cellular Reprogramming ◽  
Hallmarks Of Cancer ◽  
Compensatory Mechanisms ◽  
Response Factors ◽  
Cancer Data ◽  
Cell Stress Response ◽  
Metabolic Output

AbstractInactivation of RB is one of the hallmarks of cancer, however gaps remain in our understanding of how RB-loss changes human cells. Here we show that pRB-depletion results in cellular reprogramming, we quantitatively measured how RB-depletion altered the transcriptional, proteomic and metabolic output of non-tumorigenic RPE1 human cells. These profiles identified widespread changes in metabolic and cell stress response factors previously linked to E2F function. In addition, we find a number of additional pathways that are sensitive to RB-depletion that are not E2F-regulated that may represent compensatory mechanisms to support the growth of RB-depleted cells. To determine whether these molecular changes are also present in RB1−/− tumors, we compared these results to Retinoblastoma and Small Cell Lung Cancer data, and identified widespread conservation of alterations found in RPE1 cells. To define which of these changes contribute to the growth of cells with de-regulated E2F activity, we assayed how inhibiting or depleting these proteins affected the growth of RB1−/− cells and of Drosophila E2f1-RNAi models in vivo. From this analysis, we identify key metabolic pathways that are essential for the growth of pRB-deleted human cells.

scholarly journals Perturbing the metabolic dynamics of myo-inositol in developing Brassica napus seeds through in vivo methylation impacts its utilization as phytate precursor and affects downstream metabolic pathways

2013 ◽  
Vol 13 (1) ◽  
pp. 84 ◽  
Author(s):  
Jinzhuo Dong ◽  
Wei Yan ◽  
Cheryl Bock ◽  
Kateryna Nokhrina ◽  
Wilf Keller ◽  
...  
Keyword(s):  
Brassica Napus ◽  
Metabolic Pathways

Partially desulfated heparin modulates the interaction between anti-protamine/heparin antibodies and platelets

2016 ◽  
Vol 115 (02) ◽  
pp. 324-332 ◽  
Author(s):  
Rabie Jouni ◽  
Heike Zöllner ◽  
Ahmad Khadour ◽  
Jan Wesche ◽  
Anne Grotevendt ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Platelet Factor ◽  
Standard Drug ◽  
Platelet Surface ◽  
Minimal Impact ◽  
Platelet Survival ◽  
Heparin Complexes ◽  
The Impact

SummaryProtamine (PRT) is the standard drug to neutralise heparin. PRT/heparin complexes induce an immune response similar to that observed in heparin-induced thrombocytopenia (HIT). Partially desulfated heparin (ODSH) was shown to interfere with anti-platelet factor 4/heparin antibodies (Abs), which are responsible for HIT. In this study, we analyse the impact of ODSH on the interaction between anti-PRT/heparin Abs and platelets. The ability of ODSH to prevent anti-PRT/heparin Ab-induced platelet destruction in vivo was investigated using the NOD/ SCID mouse model. ODSH improved platelet survival in the presence of PRT, heparin and anti-PRT/heparin Abs (median platelet survival after 300 minutes (min) with 20 μg/ml ODSH: 75 %, range 70–81 % vs without ODSH: 49%, range 44–59%, p=0.006). Furthermore, when ODSH was applied 60 min after Ab injection platelet survival was improved (median platelet survival after 300 min with ODSH: 83 %, range 77–93 % vs without ODSH: 59 %, range 29–61 %, p=0.02). In in vitro experiments ODSH inhibited platelet activation at concentrations > 16 μg/mL (p< 0.001), as well as PRT/heparin complex binding to platelets (mean fluorescence intensity [MFI] without ODSH: 85 ± 14 vs with ODSH: 15 ± 0.6, p=0.013). ODSH also displaced pre-bound complexes from the platelet surface (MFI without ODSH: 324 ± 43 vs with 32 μg/ml ODSH: 53 ± 9, p< 0.001). While interfering with platelet activation by anti-PRT/heparin Abs, up to a concentration of 16 μg/ml, ODSH had only minimal impact on neutralisation of heparin by PRT. In conclusion, our study shows that ODSH is able to inhibit platelet activation and destruction suggesting a potential clinical use to reduce anti-PRT/heparin Ab-mediated adverse effects.

scholarly journals In Silico Investigation of Mitragynine and 7-Hydroxymitragynine Metabolism

2019 ◽  
Author(s):  
Taweetham Limpanuparb ◽  
Rattha Noorat ◽  
Yuthana Tantirungrotechai
Keyword(s):  
Gas Phase ◽  
In Silico ◽  
Metabolic Pathways ◽  
Experimental Studies ◽  
Medicinal Uses ◽  
Detection Techniques ◽  
Mass Spectrom ◽  
Gibbs Energies ◽  
In Silico Study

Abstract Objective: Mitragynine is the main active compound of Mitragyna speciose (Kratom in Thai). The understanding of mitragynine derivative metabolism in human body is required to develop effective detection techniques in case of drug abuse or establish an appropriate dosage in case of medicinal uses. This in silico study is based upon in vivo results in rat and human by Philipp et al. (J. Mass Spectrom., 2009, 44, 1249.) Results: The gas-phase structures of mitragynine, 7-hydroxymitragynine and their metabolites were obtained by quantum chemical method at B3LYP/6-311++G(d,p) level. Results in terms of standard Gibbs energies of reaction for all metabolic pathways are reported with solvation energy from SMD model. We found that 7-hydroxy substitution leads to changes in reactivity in comparison to mitragynine: position 17 is more reactive towards demethylation and conjugation to a glucuronide and position 9 is less reactive towards conjugation to a glucuronide. Despite the changes, position 9 is the most reactive for demethylation and position 17 is the most reactive for conjugation to a glucuronide for both mitragynine and 7-hydroxymitragynine. Our results suggest that 7-hydroxy substitution could lead to different metabolic pathways and raise an important question for further experimental studies of this more potent derivative.

scholarly journals Interactions Between Ephedra sinica and Prunus armeniaca: From Stereoselectivity to Deamination as a Metabolic Detoxification Mechanism of Amygdalin

2021 ◽  
Vol 12 ◽  
Author(s):  
Yan Qin ◽  
Shanshan Wang ◽  
Qiuyu Wen ◽  
Quan Xia ◽  
Sheng Wang ◽  
...  
Keyword(s):  
Rat Liver ◽  
Metabolic Pathways ◽  
Liver Microsomes ◽  
Prunus Armeniaca ◽  
Rat Liver Microsomes ◽  
Microbial Enzymes ◽  
Ephedra Sinica ◽  
Metabolic Detoxification ◽  
Detoxification Pathway

Mahuang–Xingren (MX, Ephedra sinica Stapf-Prunus armeniaca L.) is a classic herb pair used in traditional Chinese medicine. This combined preparation reduces the toxicity of Xingren through the stereoselective metabolism of its main active ingredient amygdalin. However, whether stereoselectivity is important in the pharmacokinetic properties of amygdalin either in the traditional decoction or in the dispensing granules is unclear. Amygdalin is hydrolyzed to its metabolite, prunasin, which produces hydrogen cyanide by degradation of the cyano group. A comprehensive study of the metabolic pathway of amygdalin is essential to better understand the detoxification process. In this article, the potential detoxification pathway of MX is further discussed with regard to herb interactions. In this study, the pharmacokinetic parameters and metabolism of amygdalin and prunasin were investigated by comparing the traditional decoction and the dispensing granule preparations. In addition, several potential metabolites were characterized in an incubation system with rat liver microsomes or gut microbial enzymes. The combination of Xingren with Mahuang reduces exposure to D-amygdalin in vivo and contributes to its detoxification, a process that can be further facilitated in the traditional decoction. From the in vitro co-incubation model, 15 metabolites were identified and classified into cyanogenesis and non-cyanogenesis metabolic pathways, and of these, 10 metabolites were described for the first time. The level of detoxified metabolites in the MX traditional decoction was higher than that in the dispensing granules. The metabolism of amygdalin by the gut microbial enzymes occurred more rapidly than that by the rat liver microsomes. These results indicated that combined boiling both herbs during the preparation of the traditional decoction may induce several chemical changes that will influence drug metabolism in vivo. The gut microbiota may play a critical role in amygdalin metabolism. In conclusion, detoxification of MX may result 1) during the preparation of the decoction, in the boiling phase, and 2) from the metabolic pathways activated in vivo. Stereoselective pharmacokinetics and deamination metabolism have been proposed as the detoxification pathway underlying the compatibility of MX. Metabolic detoxification of amygdalin was quite different between the two combinations, which indicates that the MX decoctions should not be completely replaced by their dispensing granules.

scholarly journals Phosphatidylcholine Synthesis Influences the Diacylglycerol Homeostasis Required for Sec14p-dependent Golgi Function and Cell Growth

2001 ◽  
Vol 12 (3) ◽  
pp. 511-520 ◽  
Author(s):  
Annette L. Henneberry ◽  
Thomas A. Lagace ◽  
Neale D. Ridgway ◽  
Christopher R. McMaster
Keyword(s):  
Cell Death ◽  
Cell Growth ◽  
Phosphatidic Acid ◽  
Metabolic Pathways ◽  
Eukaryotic Cells ◽  
Kennedy Pathway ◽  
Phosphatidylcholine Synthesis ◽  
Long Chain

Phosphatidylcholine and phosphatidylethanolamine are the most abundant phospholipids in eukaryotic cells and thus have major roles in the formation and maintenance of vesicular membranes. In yeast, diacylglycerol accepts a phosphocholine moiety through aCPT1-derived cholinephosphotransferase activity to directly synthesize phosphatidylcholine. EPT1-derived activity can transfer either phosphocholine or phosphoethanolamine to diacylglcyerol in vitro, but is currently believed to primarily synthesize phosphatidylethanolamine in vivo. In this study we report that CPT1- and EPT1-derived cholinephosphotransferase activities can significantly overlap in vivo such that EPT1 can contribute to 60% of net phosphatidylcholine synthesis via the Kennedy pathway. Alterations in the level of diacylglycerol consumption through alterations in phosphatidylcholine synthesis directly correlated with the level of SEC14-dependent invertase secretion and affected cell viability. Administration of synthetic di8:0 diacylglycerol resulted in a partial rescue of cells fromSEC14-mediated cell death. The addition of di8:0 diacylglycerol increased di8:0 diacylglycerol levels 20–40-fold over endogenous long-chain diacylglycerol levels. Di8:0 diacylglcyerol did not alter endogenous phospholipid metabolic pathways, nor was it converted to di8:0 phosphatidic acid.

Metabolic pathways for ketone body production. Carbon-13 NMR spectroscopy of rat liver in vivo using carbon-13-multilabeled fatty acids

Biochemistry ◽  
1986 ◽  
Vol 25 (22) ◽  
pp. 6799-6807 ◽  
Author(s):  
Claudia Pahl-Wostl ◽  
Joachim Seelig
Keyword(s):  
Fatty Acids ◽  
Nmr Spectroscopy ◽  
Rat Liver ◽  
Metabolic Pathways ◽  
Ketone Body ◽  
Body Production

Characterization of Metabolites of α-mangostin in Bio-samples from SD Rats by UHPLC-Q-Exactive Orbitrap MS

2021 ◽  
Vol 22 ◽  
Author(s):  
Fan Dong ◽  
Shaoping Wang ◽  
Ailin Yang ◽  
Haoran Li ◽  
Pingping Dong ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Garcinia Mangostana ◽  
Sd Rats ◽  
Metabolic Route ◽  
Wide Range ◽  
New Strategy ◽  
Q Exactive ◽  
Orbitrap Ms

Background: α-mangostin, a typical xanthone, often exists in Garcinia mangostana L. (Clusiaceae). α-mangostin was found to have a wide range of pharmacological properties. However, its specific metabolic route in vivo remains unclear, while these metabolites may accumulate to exert pharmacological effects, too. Objective: This study aimed to clarify the metabolic pathways of α-mangostin after oral administration to the rats. Methods: Here, an UHPLC-Q-Exactive Orbitrap MS was used for the detection of potential metabolites formed in vivo. A new strategy for the identification of unknown metabolites based on typical fragmentation routes was implemented. Results: A total of 42 metabolites were detected, and their structures were tentatively identified in this study. The results showed that major in vivo metabolic pathways of α-mangostin in rats included methylation, demethylation, methoxylation, hydrogenation, dehydrogenation, hydroxylation, dehydroxylation, glucuronidation, and sulfation. Conclusions: This study is significant to expand our knowledge of the in vivo metabolism of α-mangostin and to understand the mechanism of action of α-mangostin in rats in vivo.

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