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Fuel Metabolism in the Fetus
Published in Emilio Herrera, Robert H. Knopp, Perinatal Biochemistry, 2020
The primary precursor of the glycerol moiety of the phospholipids is dihydroxyacetone phosphate (DHAP) produced by glycolysis. DHAP will subsequently be reduced to yield glycerol-3 phosphate. Theoretically, the latter molecule can also be produced from glycerol by glycerokinase, but the concentration of glycerol in the fetal plasma is very low and its net uptake by the lung is also low, compared to glucose. Moreover, glycerokinase activity is not well developed in the fetal lung. This situation underlines the importance of a sustained rate of glycolysis for phospholipid biosynthesis.
Dihydroxyacetone phosphate and pyruvate
Published in Linda M. Castell, Samantha J. Stear (Nottingham), Louise M. Burke, Nutritional Supplements in Sport, Exercise and Health, 2015
Dihydroxyacetone phosphate (DHAP) and pyruvate are three-carbon metabolites in the glycolytic pathway. In skeletal muscle, the glycolytic pathway metabolises glucose from the blood and stored glycogen. DHAP is formed at an intermediate step, and pyruvate is produced in the final step of glycolysis. During aerobic exercise, pyruvate enters the mitochondrion and is oxidised to produce ATP. It is not immediately clear how ingesting oral doses of DHAP/pyruvate could influence athletic performance, as it is unlikely that the ingested compounds could reach skeletal muscle and have a direct effect on metabolism. Pyruvate undergoes acid hydrolysis in the stomach and gut with the liberation of carbon dioxide gas, and ingestion of large amounts of pyruvate results in gastrointestinal distress (Morrison et al., 2000). In addition, the pyruvate that is absorbed into the blood could be taken up and stored by the liver, as even the highest tolerable acute dose of pyruvate (~25g) represents a small amount of glucose (~12.5g). In support of this, no increases in whole blood and plasma pyruvate were reported during a four-hour period after the acute ingestion of 7, 15 and 25g doses of pyruvate (Morrison et al., 2000). It is not clear what happens to the ingested DHAP. Typically, a more successful approach is the ingestion of the six-carbon molecule glucose which has been repeatedly shown to accumulate in the blood and be taken up and oxidised by skeletal muscle (Jeukendrup et al., 1995).
Hodgkin lymphoma
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2014
Beate Klimm, Dennis A. Eichenauer, Andreas Engert
In the follow-up trial conducted by the GSHG, the EORTC, the EBMT and the Spanish Grup per l’Estudi dels Linfomes de Catalunya i Balears (GELCAB), all patients enrolled initially received two cycles of DHAP (dexamethasone, high-dose ara-C, cisplatin). Patients responding to DHAP were randomized between high-dose BEAM followed by ASCT and a sequential high-dose program consisting of cyclophosphamide, methotrexate/vincristine, etoposide and BEAM followed by ASCT. At a median observation of 42 months, no differences between treatment arms in terms of FFTF and OS were detectable. Thus, the less toxic approach consisting of two cycles of DHAP or other salvage protocols such as IGEV (ifosphamide, gemcitabine, etoposide, vinblastine) and ICE (ifosphamide, carboplatin, etoposide) followed by high-dose chemotherapy and ASCT remains standard of care in the treatment of patients with relapsed HL.51,52
Does maintenance therapy have a role in mantle cell lymphoma treatment?
Published in Expert Review of Hematology, 2018
These trials suggest a mixed picture for the role of rituximab maintenance. Maintenance rituximab following an induction regimen of R-DHAP consolidated with ASCT in younger patients has been established by the LyMA trial**. Evidence also supports the use of maintenance rituximab following R-CHOP induction in newly diagnosed older patients**. Although there is a suggestion of a benefit of maintenance rituximab following an induction regimen of R-FCM for R/R patients, the evidence is less clear with no statistical difference observed in OS. However, as the schedule and duration of rituximab differed in each of these trials it’s not clear what is the optimal length of maintenance treatment. The choice of induction chemotherapy regimen appears to have an impact on the utility of maintenance rituximab as no benefit was observed when rituximab maintenance was administered following B-R or FCR based induction*. Despite this, where evidence supports maintenance rituximab, it’s low toxicity profile lends itself to prolonged use and makes it suitable for maintenance therapy.
Repurposing of rabeprazole as an anti-Trypanosoma cruzi drug that targets cellular triosephosphate isomerase
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Itzhel García-Torres, Ignacio De la Mora-De la Mora, Gabriel López-Velázquez, Nallely Cabrera, Luis Antonio Flores-López, Ingeborg Becker, Juliana Herrera-López, Roberto Hernández, Ruy Pérez-Montfort, Sergio Enríquez-Flores
We have demonstrated that Rbz targets the glycolytic enzyme TIM in T. cruzi epimastigotes, leading to almost complete inhibition of enzymatic activity. Even though this organism has the glycosomal enzyme that degrades DHAP to glycerol 3-phosphate (NADH-dependent glycerol-3-phosphate dehydrogenase)23 the accumulation of DHAP occurs due to the interruption of TIM activity. This is highly relevant since in conditions of deficiency or deletion of TIM, an excessive accumulation of DHAP occurs52,80 which causes its spontaneous degradation and forms the highly toxic metabolite methylglyoxal (MGO)81. At low concentrations, MGO can help cell growth, but at high concentrations, it can be toxic and causes cell death82. Although T. cruzi has detoxification mechanisms such as the glyoxalase system (Glyoxalases 1 and 2), we found that the intracellular MGO levels increased up to almost 10 times the control level when treated with Rbz at the maximum concentration (Figure 4). This suggests that the glyoxalase system and other detoxifying enzymes failed to remove this toxic metabolite. In this regard, another study showed that the exogenous addition of MGO to T. cruzi epimastigotes caused cell death in these organisms, with an EC50 of 171 μM83. Interestingly, our study showed that MGO levels of up to 0.37 μM per million epimastigotes were obtained (Figure 4), which is significantly lower than that reported by Greig in 2009. However, these levels were generated intracellularly due to treatment with Rbz with concomitant inactivation of cellular TIM, in contrast to the exogenous MGO in the other study.
Evaluating dasiglucagon as a treatment option for hypoglycemia in diabetes
Published in Expert Opinion on Pharmacotherapy, 2020
Shujuan Li, Ying Hu, Xueying Tan, Dongwei Wang, Jingbo Hu, Ping Zou, Li Wang
Actually, a randomized, two-period crossover clinical trial has already demonstrated that both dasiglucagon and marketed glucagon delivered by a DHAP system showed similar mild or moderate adverse effects including nausea and hypoglycemia, etc. [26]. No anti-drug antibody to either drug was detected, and no blocking of infusion set occurred. The trial directly suggested the safety of dasiglucagon delivered by a DHAP device.