Liver gamma-cystathionase activity increases in rats during lactation; its inhibition due to propargylglycine is followed by a significant decrease in lactation. This is reversible by N-acetylcysteine administration. To study the role of liver gamma-cystathionase and the intertissue flux of glutathione during lactation, we used lactating and virgin rats fed liquid diets. Virgin rats were divided into two groups as follows: one group was fed daily a diet containing the same amount of protein that was consumed the previous day by lactating rats (high protein diet-fed rats); the other virgin group was fed the normal liquid diet (control). The expression and activity of liver gamma-cystathionase were significantly greater in lactating rats and in high protein diet-fed virgin rats compared with control rats. The total glutathione [reduced glutathione (GSH) + oxidized glutathione (GSSG)] released per gram of liver did not differ in lactating rats or in high protein diet-fed rats, but it was significantly higher in these two groups than in control virgin rats. Liver size and the GSH + GSSG released by total liver were significantly higher in lactating rats than in high protein diet-fed virgin rats, and this difference was similar to the amount of glutathione taken up by the mammary gland (454.2 +/- 36.0 nmol/min). The uptake of total glutathione by the lactating mammary gland was much higher than the uptakes of free L-cysteine and L-cystine, which were negligible. These data suggest that the intertissue flux of glutathione is an important mechanism of L-cysteine delivery to the lactating mammary gland, which lacks gamma-cystathionase activity. This emphasizes the physiologic importance of the increased expression and activity of liver gamma-cystathionase during lactation.
Conflict of interest: COI declared -see note COI notes: PG reports speaker honoraria from Novartis and Abbvie and fees from Novartis and Abbvie for participation on advisory boards. AMV has personal fees as advisory bord and speaker fee from AOP Orphan Pharmaceuticals and Novartis. AR has personal fees as advisory board from Astellas, Amgen, Celgene BMS, Gilead, Italfarmaco, Novartis, Omeros, Roche, and Sanofi. TB declares personal fees as advisory bord from AOP Orphan Pharmaceuticals, Italfarmaco, and Novartis, outside the submitted work. The remaining authors declare no competing financial interests. Preprint server: No;Author contributions and disclosures: PG interpreted the data, and wrote the brief report. TB conceived and designed the study, supervised the analysis and critically revised the brief report. AG and AC contributed to dataset preparation, planned and performed statistical analyses. AM directed the project. AMV interpreted the data and critically revised the brief report.
To study the fate of L-cysteine and amino acid homeostasis in liver after the inhibition of the transsulfuration pathway, rats were treated with propargylglycine (PPG). At 4 h after the administration of PPG, liver cystathionase (EC 4.4.1.1) activity was undetectable, L-cystathionine levels were significantly higher, L-cysteine was unchanged and GSH concentration was significantly lower than values found in livers from control rats injected intraperitoneally with 0.15 M-NaCl. The hepatic levels of amino acids that are intermediates of the urea cycle, L-ornithine, L-citrulline and L-arginine and blood urea were significantly greater. Urea excretion was also higher in PPG-treated rats when compared with control rats. These data suggest a stimulation of ureagenesis in PPG-treated rats. The inhibition of y-cystathionase was reflected in the blood levels of amino acids, because the Lmethionine : L-cyst(e)ine ratio was significantly higher in PPG-treated rats than in control rats; blood concentration of cystathionine was also greater. Histological examination of liver and kidney showed no changes in PPG-treated rats when compared with controls. The administration of Nacetylcysteine (NAC) to PPG-treated rats reversed the changes in blood urea and in liver GSH. These data suggest that when liver L-cysteine production was impaired by the blockage of the transsulfuration pathway, the concentration of this amino acid was maintained mainly by an increase in protein degradation and by a depletion in GSH concentration that may spare L-cysteine. Liver: Cysteine: Propargylglycine: CystathionaseThe maintenance of intracellular L-cysteine concentration in liver is achieved by several mechanisms: (1) the trans-sulfuration pathway, (2) the uptake from plasma, (3) proteolysis, (4) the rate of L-cysteine incorporation into GSH and (5) the conversion to taurine. The availability of L-cysteine is the rate-limiting step for the synthesis of GSH by mammalian cells (Tateishi et al. 1974;Beutler, 1989); therefore, the capacity of tissues, mainly the liver, to synthesize L-cysteine from L-methionine is important to cell homeostasis (Rose & Wixom, 1955). It has been estimated that 5040% of the dietary L-methionine requirements can be dispensed with if the diet is supplemented with L-cysteine, and for this reason the latter has been called a conditionally indispensable amino acid (Laidlaw & Kopple, 1987) in those situations in which cystathionase activity is low.The daily turnover of L-methionine which includes the incorporation into and release from protein and the conversion of methionine to homocysteine and its remethylation, is approximately double the dietary intake (Nunn, 1987), therefore the recycling of Lmethionine from homocysteine is important (Finkelstein, 1990). However, homocysteine is available at https://www.cambridge.org/core/terms. https://doi
Despite emerging molecular information on chronic myelomonocytic leukemia (CMML), patient outcome remains unsatisfactory and little is known about the transformation to acute myeloid leukemia (AML). In a single-center cohort of 219 CMML patients, we explored the potential correlation between clinical features, gene mutations, and treatment regimens with overall survival (OS) and clonal evolution into AML. The most commonly detected mutations were TET2, SRSF2, ASXL1, and RUNX1. Median OS was 34 months and varied according to age, cytogenetic risk, FAB, CPSS and CPSS-Mol categories, and number of gene mutations. Hypomethylating agents were administered to 37 patients, 18 of whom responded. Allogeneic stem cell transplantation (alloSCT) was performed in 22 patients. Two-year OS after alloSCT was 60.6%. Six patients received targeted therapy with IDH or FLT3 inhibitors, three of whom attained a long-lasting response. AML transformation occurred in 53 patients and the analysis of paired samples showed changes in gene mutation status. Our real-world data emphasize that the outcome of CMML patients is still unsatisfactory and alloSCT remains the only potentially curative treatment. However, targeted therapies show promise in patients with specific gene mutations. Complete molecular characterization can help to improve risk stratification, understand transformation, and personalize therapy.
Germline predisposition in acute myeloid leukemia (AML) has gained importance in recent years due to a non-negligible frequency and impact on management of patients and their relatives. Risk alleles for AML development may be present in patients without a clinical suspicion of hereditary hematologic malignancy syndrome. In this study we investigated the presence of germline variants (GV) in 288 genes related to cancer predisposition in 47 patients with available paired tumor-normal material, namely bone marrow stroma cells (BMSC, n=29), post-remission bone marrow (PRBM, n=17) and saliva (n=1). These patients correspond to two broad AML categories with heterogeneous genetic background (AML myelodysplasia-related and AML defined by differentiation) and none of them had phenotypic abnormalities, previous history of cytopenia nor strong cancer aggregation. We found 11 pathogenic or likely pathogenic variants, six affecting genes related to autosomal dominant cancer predisposition syndromes (ATM, DDX41 and CHEK2) and 5 related to autosomal recessive bone marrow failure syndromes (FANCA, FANCM, SBDS, DNAJC21 and CSF3R). We did not find differences in clinical characteristics nor outcome between GV carriers vs non-carriers. Further studies in unselected AML cohorts are needed to determine GV incidence and penetrance and, in particular, to clarify the role of ATM nonsense mutations in AML predisposition.
Background and aims: Porto-sinusoidal vascular disease (PSVD) is a rare disease that requires excluding cirrhosis and other causes of portal hypertension for its diagnosis because it lacks a specific diagnostical test. Although it has been occasionally associated with autoimmune diseases, the pathophysiology of PSVD remains unknown.The aim of this study was to evaluate the potential role of autoimmunity in the pathophysiology and diagnosis of PSVD.Methods: Thirty-seven consecutive patients with PSVD and 39 with cirrhosis matched by gender, signs of portal hypertension and liver function were included (training set). By using Indirect Immunofluorescence, ELISA and slot-blot methods data 22 autoantibodies were identified in patients with PSVD and cirrhosis. Presence of antiendothelial cells antibodies (AECA) was assayed by a cell-based ELISA. Thirty-one
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