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Abstract: As a functional component of erythrocyte hemoglobin, iron is essential for oxygen delivery to all tissues in the body. The liver-derived peptide hepcidin is the master regulator of iron homeostasis. During anemia, the erythroid hormone erythroferrone regulates hepcidin synthesis to ensure the adequate supply of iron to the bone marrow for red blood cell production. However, mounting evidence suggested that another factor may exert a similar function. We identified the hepatokine fibrinogen-like 1 (FGL1) as a previously undescribed suppressor of hepcidin that is induced in the liver in response to hypoxia during the recovery from anemia, and in thalassemic mice. We demonstrated that FGL1 is a potent suppressor of hepcidin in vitro and in vivo. Deletion of Fgl1 in mice results in higher hepcidin levels at baseline and after bleeding. FGL1 exerts its activity by directly binding to bone morphogenetic protein 6 (BMP6), thereby inhibiting the canonical BMP-SMAD signaling cascade that controls hepcidin transcription., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Aims: Several medicinal treatments for avoiding postoperative ileus (POI) after abdominal surgery have been evaluated in randomized controlled trials (RCTs). This network meta-analysis aimed to explore the relative effectiveness of these different treatments on ileus outcome measures., Methods: A systematic literature review was performed to identify RCTs comparing treatments for POI following abdominal surgery. A Bayesian network meta-analysis was performed. Direct and indirect comparisons of all regimens were simultaneously compared using random-effects network meta-analysis., Results: A total of 38 RCTs were included in this network meta-analysis reporting on 6371 patients. Our network meta-analysis shows that prokinetics significantly reduce the duration of first gas (mean difference [MD] = 16 h; credible interval -30, -3.1; surface under the cumulative ranking curve [SUCRA] 0.418), duration of first bowel movements (MD = 25 h; credible interval -39, -11; SUCRA 0.25) and duration of postoperative hospitalization (MD -1.9 h; credible interval -3.8, -0.040; SUCRA 0.34). Opioid antagonists are the only treatment that significantly improve the duration of food recovery (MD -19 h; credible interval -26, -14; SUCRA 0.163)., Conclusion: Based on our meta-analysis, the 2 most consistent pharmacological treatments able to effectively reduce POI after abdominal surgery are prokinetics and opioid antagonists. The absence of clear superiority of 1 treatment over another highlights the limits of the pharmacological principles available., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Introduction: The medical identification of an addiction (use disorder) often results in inpatient admission with a view to its definitive suspension. However, for other chronic diseases, inpatient admission is indicated for specific situations and the objective is not the definitive suspension of the chronic disease. Our goal was to clarify addiction as a chronic disease and to determine explicit indications for inpatient admission., Method: Three-stage face validity study: (1) from the analysis of consensual definitions, search by the subset theory whether addiction can be considered as a chronic disease; (2) Develop generic indications for inpatient admissions based on the analysis of chronic disease care pathways validated by the HAS (French Health Agency) and apply them to addiction; (3) Validate by Delphi expert consensus method the determined indications., Results: Step (1) showed that the definition of addiction allowed to include it in that of chronic disease. Step (2) determined 7 indications for inpatient admission of a patient with a chronic disease, and its application to addiction identified 15 indications for inpatient admission of a patient with addiction. In step (3), the Delphi method yielded consensus on 14 of the 15 indications., Conclusion: By clarifying addiction as a chronic disease, we were able to determine 14 indications for inpatient admission of a person with an addiction and to distinguish them from the long-term care of addiction. These explicit indications can help the general practitioner or community psychiatrist to better manage patients with addiction on the basis of their expertise with chronic diseases management., (Copyright © 2020 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

ABSTRACT Field observations were conducted from 1998 to 2001 at the International Cocoa Genebank, Trinidad, to evaluate 57 cacao clones for resistance to black pod (BP) and witches'-broom (WB) diseases (caused by Phytophthora sp. and Crinipellis perniciosa, respectively). Each month ripe pods were harvested and the number of healthy and diseased was recorded. The number of brooms on vegetative shoots was recorded three times a year on selected branches. Twenty-three clones showed less than 10% of infection for both BP and WB on pods. Among those, eight clones showed an absence of brooms on the observed branches: IMC 6, MAN 15/60 [BRA], PA 67 [PER], PA 195 [PER], PA 218 [PER], PA 296 [PER], PA 303 [PER], and POUND 32/A [POU]. Broad-sense heritability was estimated at 0.38 and 0.57 for WB disease on pods and shoots, respectively, and at 0.51 for BP disease. Genetic correlation between WB disease on pods and on shoots was low and estimated at 0.39, whereas the correlation between WB and BP diseases on pods was 0.48. To choose putative parents for breeding schemes, it is suggested that clones are first assessed for their level of resistance to WB on shoots, and the most promising individuals are screened for BP with a detached pods test. Further studies are needed to confirm whether the level of resistance to WB on pods can be predicted using an early test on seedlings.

Objective: Bile salt-dependent lipase (BSDL), a lipolytic enzyme secreted in the duodenum by pancreatic acinar cells, has been detected in the serum of all patients and in atheromatous plaque, suggesting its potential implication in vascular pathophysiology., Methods and Results: In vitro pancreatic BSDL evokes human umbilical vein endothelial cell (HUVEC) proliferation and chemotactic migration. BSDL at mitogen concentration is capable to heal wounded HUVEC monolayer and to promote capillary network formation. HUVEC proliferation depends on the displacement of basic fibroblast growth factor and vascular endothelial growth factor from the extracellular matrix and the activation of extracellular signal-regulated kinases (ERK1/2), p38 mitogen-activated protein kinase, and focal adhesion kinase signaling pathways., Conclusions: For the first time to our knowledge, it is suggested that circulating BSDL could be involved in pathophysiological angiogenesis. We delineate the in vitro effects of pancreatic BSDL on endothelial cells, and we show that BSDL promotes proliferation, migration, capillary network formation, and wound-healing of HUVECs via the displacement of bFGF and VEGF from the ECM, suggesting that BSDL could be involved in angiogenesis.

This case report describes a 68-year-old woman presenting with flecainide induced syncope due to torsades de pointes (TP) ventricular tachycardia. Before TP onset, the QTc interval reached 680 ms without changes in QRS duration. None of the usual triggers were found. Prolongation of QT under flecaïnide is exceptional and the occurrence of TP without concurrent triggers has not been reported in the literature.

In this paper, we report, for the first time, the localization of the phosphorylation site of the fetoacinar pancreatic protein (FAPP), which is an oncofetal variant of the pancreatic bile salt-dependent lipase. Using Chinese hamster ovary (CHO) cells transfected with the cDNA encoding FAPP, we radiolabeled the enzyme with (32)P, and then the protein was purified by affinity chromatography on cholate-immobilized Sepharose column and submitted to a CNBr hydrolysis. Analysis of peptides by high pressure liquid chromatography, associated with the radioactivity profile, revealed that the phosphorylation site is located at threonine 340. Site-specific mutagenesis experiments, in which the threonine was replaced by an alanine residue, were used to invalidate the phosphorylation of FAPP and to study the influence of the modification on the activity and secretion of the enzyme. These studies showed that CHO cells, transfected with the mutated cDNA of FAPP, kept all of their ability to synthesize the protein, but the loss of the phosphorylation motif prevented the release of the protein in the extracellular compartment. However, the mutated enzyme, which was sequestrated in the transfected CHO cells, remains active on bile salt-dependent lipase substrates.

Bile salt-dependent lipase (BSDL, EC 3.1.1.13) is a lipolytic enzyme normally secreted by the pancreatic acinar cell. Co- and post-translational modifications, such as N- and O-linked glycosylation, regulate the secretion of this enzyme; therefore it was of first importance to determine the behaviour of BSDL under conditions that impaired its secretion. Using AR4-2J pancreatic cells as model, we showed, particularly when BSDL secretion is impaired, that proteasome inhibitors increased the amount of intracellular BSDL, suggesting that the proteasome is involved in the degradation of this protein. This was strengthened by the detection of ubiquitinated BSDL and of degradation product. Our results suggested that both ubiquitination and degradation of the enzyme occurred at the level of the cytosolic side of microsome membranes. ATP hydrolysis appears essential in ubiquitinated BSDL association with membranes and degradation. Furthermore, under normal secretory conditions, we have shown that a fraction of ubiquitinated BSDL is neither O-glycosylated nor N-glycosylated, suggesting that the N-glycosylation-deficient proteasome substrate does not reach the Golgi and could be degraded by the ER-associated degradation machinery. However, another fraction of ubiquitinated BSDL that is deficient in O-glycosylation, carries out endoglycosidase H-insensitive N-linked glycans, meaning that a second system, that detects abnormal BSDL molecules, could also operate at the level of the Golgi compartment. Consequently, it appears that impairment of BSDL secretion consecutive to secretion inhibition or to a deficient glycosylation leads to the proteasome-ubiquitin-dependent degradation of the protein. Therefore, this pathway is part of the quality control involved in BSDL secretion.

Bile-salt-dependent lipase (BSDL; EC 3.1.1.13) is an enzyme expressed by the pancreatic acinar cell and secreted as a component of the pancreatic juice. During its route towards secretion, BSDL is associated with intracellular membranes by means of a multiprotein folding complex, which includes the glucose-regulated protein of 94 kDa (Grp94). We have postulated that the association of BSDL with membranes is required for the complete O-glycosylation of the protein, which diverts BSDL from a degradation route and consequently allows its secretion. To further characterize the role of Grp94 in BSDL secretion, we have studied the effect of a ribozyme specifically targeted to Grp94 mRNA. This ribozyme has been transfected into AR4-2J cells, and we have shown that a decrease in Grp94 expression leads to a concomitant decrease in BSDL secretion and expression. Geldanamycin (GA), which alters Grp94 functions, also affects the release of BSDL into the culture medium of AR4-2J cells. BSDL expressed in GA-treated AR4-2J cells is unstable. Furthermore, under conditions that decrease the level of BSDL secretion, no intracellular accumulation of the enzyme was observed, suggesting that BSDL that cannot associate with (or be structured by) Grp94 could be rapidly degraded. We have further shown that this degradation probably occurs via the ubiquitin-dependent pathway. Altogether, these results indicate that Grp94 has a pivotal role in BSDL folding and in the sorting of this pancreatic enzyme.

In this article, we report the nucleotide sequence of the cDNA encoding an isoform of bile-salt-dependent lipase (BSDL) expressed by human hepatoma cells. The BSDL is a 100-kDa glycoprotein normally expressed by the human pancreas. Using a polyclonal antibody raised against an internal peptide located between Ile(327) and Glu(350) of the human pancreatic BSDL, we have immunodetected an isoform of human pancreatic BSDL, with an apparent molecular mass of about 62 kDa. This isoform of BSDL was mainly associated with the cytosol of a human hepatoma cell line (HepG2), the remaining protein being found in the microsome fraction. In addition, esterolytic activity on p-nitrophenyl hexanoate measured in microsomes and cytosol appeared very low and was weakly stimulated by bile salts, such as taurocholate. In contrast to human pancreatic BSDL, which is secreted as a component of pancreatic juice, this isoform appeared to be retained in the HepG2 cells. Reverse transcription, followed by PCR and amplification, performed on RNA extracted from HepG2 cells using specific primers hybridizing to the sequence coding for the entire normal human pancreatic BSDL, allowed us to amplify a 1. 7-kb transcript that appeared to be 0.5 kb shorter than the transcript of the pancreatic enzyme (2.2 kb). From the sequence of the transcript thus obtained, a protein with a molecular mass of 62 kDa might be predicted, which is in good agreement with the size of the isoform of BSDL immunodetected in HepG2 cells. The N-terminal amino-acid sequence, deduced from the 1.7-kb transcript sequence, matched that of the pancreatic BSDL. However, the C-terminal domain appeared truncated, bearing only a single mucin-like sequence compared with sixteen for the human pancreatic BSDL. The actual intracellular function of this human BSDL hepatoma isoform remains to be elucidated.

The mechanisms by which ethanol administration alters pancreatic function are unknown. We have evaluated the effects of chronic ethanol treatment on secretion of a digestive enzyme: the bile salt-dependent lipase (BSDL), by the rat pancreatic cell line AR4-2J (as a model). We report that ethanol (50-300 mM) in culture medium induced a rise, in secreted and intracellular BSDL, that was a function of the duration of treatment and of the ethanol concentration. This effect was not abolished by pyrazole, which suggests a direct effect of ethanol. We have further established that the increase of BSDL activity was due to an enhanced biosynthesis of the enzyme consecutive to a major steady-state level of mRNA encoding BSDL. Also, the subcellular localization showed a specific accumulation of BSDL in the cytosolic fraction of cells chronically treated with ethanol. Given the enzymatic properties of BSDL, all these data could have some physiological consequences regarding the digestive function, plasma lipid metabolism and intracellular cholesterol homeostasis.

Pancreatic bile salt-dependent lipase (BSDL) hydrolyzes cholesteryl esters, triglycerides and phospholipids. BSDL is also capable of transferring free fatty acid to cholesterol. BSDL has been detected in many cells including fetal and tumor cells, hepatocytes, macrophages and eosinophils and in tissues such as adrenal glands and testes. The enzyme may be secreted or located within subcellular compartments such as the endoplasmic reticulum or the cytosol. Although the role of the secreted enzyme is well documented, that of the intracellular form(s) is still hypothetical. In the present study, we addressed the effects of BSDL on cell lipid metabolism. For that purpose, the cDNA of rat BSDL was transfected into CHO K1 cells (CHO K1-BSDL clone) which were then loaded with [3H]oleic acid. The results demonstrate that the transfected BSDL is secreted; in spite of that, a large fraction of catalytically active BSDL is found in cell lysate. The lipid metabolism of transfected cells is affected and BSDL induces an enhanced incorporation of [3H]oleic acid in cholesteryl esters whereas fatty acid incorporation in phosphatidylcholine is decreased. These effects were particularly important in the cytosol of transfected cells where transfected BSDL preferentially locates. These data suggested that BSDL could be implicated in the cycle of the cellular homeostasis of cholesterol which is particularly affected in tumoral cells leading to cholesteryl ester storage within cytosolic lipid droplets.

Exposure of rat reticulocytes to Nigericin produced a selective modulation of fatty acid incorporation into sphingomyelin (SM) of the cell membrane, via changes in SM acylation kinetics. At physiological fatty acid concentration, Nigericin accelerated 8-fold SM acylation by decreasing the apparent K(m) for oleate from 14.7 microM to 2.0 microM. The response was diminished in high K(+)-containing media, suggesting an effect of Nigericin as K+ transporter. This constitutes a novel piece of evidence for the important role of ions in SM metabolism.

By using a tracer method, we demonstrate that short-term in vitro exposure of intact rat reticulocytes to ethanol elicits a biphasic response of cell-bound Mg(2+)-dependent phosphatidate phosphohydrolase (PAP). An initial concentration-dependent (200-750 mM) activity decrease is rapidly (< 10 min) followed by reversal of the inhibition in the presence of ethanol, suggesting the development of a cell resistance to the inhibitory agent. Addition to the cell suspension of propranolol (100 microM), a known PAP inhibitor, does elicit PAP inhibition but unlike ethanol, inhibition is not followed by a return with time to control value. Ethanol-induced inhibition of cell-bound PAP was also demonstrated in cell-free extracts, where the Mg(2+)-dependent activity was decreased both in the particulate and soluble fractions. In the intact cells, the transient PAP inhibition occurs in concomitance with an overall increase in total glycerolipid biosynthesis, which is constant over 60-min incubation. We suggest that the biphasic mode of response to ethanol of Mg(2+)-dependent PAP activity may play a role in the mechanism of membrane adaptation to ethanol, and thereby to the pathogenesis of alcoholism.

Earlier reports have shown that, in human and rat red blood cells (RBC), ethanol modulates acylation reaction sin several membrane glycerolipid components. Little is known, however, about the kinetics and the mechanisms involved in the acylation changes. In the present study, we show that short-term in vitro exposure of intact rat reticulocytes to ethanol differentially modifies within minutes the incorporation of [3H]oleic acid in glycerolipids. A concentration-dependent inhibition of acyl incorporation was measured in phosphatidylcholine (PC) and phosphatidylethanolamine (PE). This effect did not involve inhibition of the corresponding acyltransferase activities and is likely to be due to ethanol-dependent decreases in phospholipase activities. In contrast, ethanol markedly stimulated [3H]oleic acid incorporation in phosphatidic acid (PA), diacylglycerol (DG) and, to a lesser extent, in triacylglycerol (TG). To determine the mechanisms of the latter increases, reticulocytes were pulsed with [14C]glycerol and assayed as a function of time for labeled biosynthetic precursors and products. We observed a very close correlation between time courses and amplitudes of the ethanol stimulation of acylation and biosynthesis reactions, suggesting that stimulation of acylation in PA, DG and TG is causally related at least partly to their increased biosynthesis. Further studies revealed that increases in glycerolipid acylation and biosynthesis in reticulocytes were: (a) readily reversible upon ethanol withdrawal; (b) detectable for clinically relevant concentration (50 mM) of ethanol; and (c) associated with concomitant increases in cell resistance to hemolysis. These changes may be relevant to the development of tolerance to ethanol.

We have investigated the patterns of incorporation of stearic, oleic, and linoleic acids into phosphatidylcholine (PC) and phosphatidylethanolamine (PE) of intact red blood cells of differing age isolated by centrifugation on discontinuous density gradient. Acylation rates of PC and PE elicited marked declines from the reticulocyte to the young erythrocyte stage followed by minimal changes of acylating potency in older cells; this biphasic decay pattern was similar with the three fatty acids. Molar acylation rates were higher for PC than for PE in reticulocytes, whereas they were comparable in erythrocytes. PC served as preferred fatty acid acceptor in circulating red blood cells, a function which was largely accounted for by PC contained in the small percentage of circulating reticulocytes. On a per cell basis, this function of PC was due to the cumulative effects of higher molar acylation rates in reticulocytes and higher content in PC over PE in the red blood cell membrane. Acylation rates in PC and PE increased with the number of unsaturated bonds in the acylating fatty acid, regardless of cell age.

Ethinyl estradiol administered in vivo to female rats resulted in a mild anemia with a 120% increase in reticulocytosis. Consistent with a previous study, the red blood cell cholesterol-to-phospholipid molar ratio was decreased by 25%, whereas fatty acyl incorporation was significantly increased into phosphatidylethanolamine (PE) and not into phosphatidylcholine (PC), the major acyl acceptor in red blood cells. Analysis of this estrogen-dependent acylation increase as a function of cell age indicated that it was not expressed in reticulocytes but in erythrocytes and was associated with cell aging. Estrogen was further shown to increase the red blood cell susceptibility to peroxidation generated by incubation with H2O2. Altogether, the results suggest that estrogen indirectly increases phospholipid acylation in red blood cells by decreasing protection against oxidative damage, thereby favoring the action of endogenous phospholipases against oxidized substrates. This occurs predominantly in PE of oldest cells because 1) PE, being more unsaturated than PC, is more sensitive to oxidation, and 2) susceptibility to oxidation increases with cell age.

The authors studied progressive changes in coronary atheromatous lesions by iterative coronarography after an average period of 2 years, and at least 1 year, in operated (50 cases with a single aortocoronary venous shunt), or non-operated patients (24 cases). The results were compared to those reported in previously published papers, using as a reference, the monthly percentage deterioration in pre-existing lesions. In the non-operated patients (24 cases), results were comparable to those obtained by some authors, and showed that the lesions deteriorated by about 10% each year. In operated patients, the authors refute the previously accepted statement that operative therapy causes a more rapid worsening of the lesions. It certainly appears to be false when the graft is occluded (17 cases); and seems to be at least premature when it is permeable (33 cases). The authors also attempted to find a correlation which could be used to assess probable evolutory changes in coronary lesions. This had previously been envisaged by Rösch, but it is difficult to establish, and further complementary studies are necessary.

Filtration is one of the classical methods for the determination of the microbial content of the air or the number of microbe-bearing particles in the ambient air. Hereby, the opinion prevails that gelatin foam filters yield better results than filters made of cellulose esters. Since gelatin filters are themselves by no means free from disadvantages, several tests were carried out under the conditions encounted in practice in two packaging rooms used for pharmaceutical preparations. The objective was to ascertain whether the customary cellulose ester filters really are less suitable for determination of the microbial content of the air than the filters made of soluble gelatin. Based on the results of various preliminary experiments, gamma-irradiated filters of cellulose nitrate, with a pore size of 0,45 micron, were selected from a range of tested membrane filters (Tables 1,2,4-6 and Fig. 1) and compared directly with the gelatin filters. The statistical evaluation of these tests showed that, under the chosen experimental conditions, both filters yielded the same count of organisms (Tables 3, 9 and 10, Figs. 2 and 3). Moreover, by means of further tests, it could be proved that neither cellulose nitrate filters with a pore size of 0,8 micron, which had undergone gamma-radiations, nor filters made of the mixed esters of cellulose, which had been treated with ethylene oxide or autoclaved, differed significantly from the selected type (Tables 5-8). This study therefore clearly demonstrates that - in addition to gelatin filters - a whole range of membrane filters made of cellulose esters yield equally good results and may be used for supervision of the microbial content of the air in closed rooms.