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

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 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.

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.

scholarly journals Effects of indole-3-carbinol on metabolic parameters and on lipogenesis and lipolysis in adipocytes 182

2009 ◽  
Vol 54 (No. 4) ◽  
pp. 182-189 ◽  
Author(s):  
M. Okulicz ◽  
I. Hertig ◽  
J. Chichłowska
Keyword(s):  
Metabolic Pathways ◽  
Direct Action ◽  
Liver Steatosis ◽  
Density Lipoprotein ◽  
Metabolic Parameters ◽  
Male Rats ◽  
Liver Cholesterol ◽  
Carbohydrate And Lipid Metabolism

: Indole-3-carbinol (I3C) was found to have possible anticarcinogenic, antioxidant and anti-atherogenic effects on the organism. So far, its influence on metabolic pathways has been unknown. This work was the first attempt to determine the carbohydrate and lipid metabolism changes <I>in vivo</I> after administration of 150 mg/kg b.wt./day I3C to male rats. Additionally, the aim of this trial was to evaluate the direct effect of I3C on basal and hormone-induced lipogenesis and lipolysis in isolated rat adipocytes at concentrations 1, 10, 100 &mu;M <I>in vitro</I>. We can corroborate that adipocytes are susceptible to the direct action of I3C. The incubation of adipocytes with I3C at the three above-mentioned concentrations resulted in its influence on restriction of glucose entry into adipocytes in the basal as well as insulin-stimulated conditions. However, it was observed that I3C at these concentrations strongly intensified basic and epinephrine-stimulated lipolysis. I3C also has a significant influence on metabolism <I>in vivo</I>. Its administration to rats caused a significant increase in the content of triglycerides and a decrease in glycogen in the liver. The considerable augmentation of glucose, triglycerides, cholesterol in high-density lipoprotein and insulin with a concomitant decrease in FFA concentrations was noted in the blood serum. I3C did not alter phospholipids, total, free, esterified cholesterol in the serum and the liver cholesterol. The results obtained <I>in vivo</I> and <I>in vivo</I> indicate that the effect of I3C is adverse for the majority of metabolic parameters which were investigated. The most important finding in this study is the effect of I3C on liver steatosis and that the observed lower lipogenesis at higher lipolysis in fat cells may be involved in the mechanism.

scholarly journals The in vivo ISGylome links ISG15 to metabolic pathways and autophagy upon Listeria monocytogenes infection

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yifeng Zhang ◽  
Fabien Thery ◽  
Nicholas C. Wu ◽  
Emma K. Luhmann ◽  
Olivier Dussurget ◽  
...  
Keyword(s):  
Listeria Monocytogenes ◽  
Metabolic Pathways ◽  
Quantitative Proteomics ◽  
Computational Analysis ◽  
Murine Models ◽  
Direct Modification ◽  
Catalytic Sites ◽  
Listeria Monocytogenes Infection

AbstractISG15 is an interferon-stimulated, ubiquitin-like protein, with anti-viral and anti-bacterial activity. Here, we map the endogenous in vivo ISGylome in the liver following Listeria monocytogenes infection by combining murine models of reduced or enhanced ISGylation with quantitative proteomics. Our method identifies 930 ISG15 sites in 434 proteins and also detects changes in the host ubiquitylome. The ISGylated targets are enriched in proteins which alter cellular metabolic processes, including upstream modulators of the catabolic and antibacterial pathway of autophagy. Computational analysis of substrate structures reveals that a number of ISG15 modifications occur at catalytic sites or dimerization interfaces of enzymes. Finally, we demonstrate that animals and cells with enhanced ISGylation have increased basal and infection-induced autophagy through the modification of mTOR, WIPI2, AMBRA1, and RAB7. Taken together, these findings ascribe a role of ISGylation to temporally reprogram organismal metabolism following infection through direct modification of a subset of enzymes in the liver.

scholarly journals In vivo efficacy and metabolism of the antimalarial cycleanine and improved in vitro antiplasmodial activity of novel semisynthetic analogues

2020 ◽  
Author(s):  
Fidelia Ijeoma Uche ◽  
Xiaozhen Guo ◽  
Jude Okokon ◽  
Imran Ullah ◽  
Paul Horrocks ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
High Performance ◽  
Antimalarial Activity ◽  
Biological Activities ◽  
Antiplasmodial Activity ◽  
Survival Times ◽  
Antiproliferative Effects ◽  
Future Evaluation

Bisbenzylisoquinoline (BBIQ) alkaloids are a diverse group of natural products that demonstrate a range of biological activities. In this study, the in vitro antiplasmodial activity of three BBIQ alkaloids (cycleanine (1), isochondodendrine (2) and 2′-norcocsuline (3)) isolated from the Triclisia subcordata Oliv. medicinal plant traditionally used for the treatment of malaria in Nigeria are studied alongside two semi-synthetic analogues (4 and 5) of cycleanine. The antiproliferative effects against a chloroquine-resistant Plasmodium falciparum strain were determined using a SYBR Green 1 fluorescence assay. The in vivo antimalarial activity of cycleanine (1) is then investigated in suppressive, prophylactic and curative murine malaria models after infection with a chloroquine-sensitive Plasmodium berghei strain. BBIQ alkaloids (1–5) exerted in vitro antiplasmodial activities with IC50 at low micromolar concentrations with the two semi-synthetic cycleanine analogues showing an improved potency and selectivity than cycleanine. At oral doses of 25 and 50mg/kg body weight of infected mice, cycleanine suppressed the levels of parasitaemia, and increased mean survival times significantly compared to the control groups. The metabolites and metabolic pathways of cycleanine (1) were also studied using high performance liquid chromatography electrospray ionization tandem mass spectrometry. Twelve novel metabolites were detected in rats after intragastic administration of cycleanine. The metabolic pathways of cycleanine were demonstrated to involve hydroxylation, dehydrogenation, and demethylation. Overall, these in vitro and in vivo results provide a basis for the future evaluation of cycleanine and its analogues as leads for further development.

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