17α-HYDROXYLASE DEFICIENCY. A COMBINATION OF HYDROXYLATION DEFECT AND REVERSIBLE BLOCKADE IN ALDOSTERONE BIOSYNTHESIS

1979 ◽  
Vol 90 (3) ◽  
pp. 490-504 ◽  
Author(s):  
D. R. Rovner ◽  
J. W. Conn ◽  
E. L. Cohen ◽  
F. G. Berlinger ◽  
D. C. Kern ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Extracellular Fluid ◽  
Plasma Renin ◽  
Hydroxyl Group ◽  
Side Chain ◽  
Hydroxylase Deficiency ◽  
Resultant Increase

ABSTRACT We have studied the hormonal secretion and excretion patterns in a patient with the XX type of 17α-hydroxylase deficiency. In the untreated state, the patient's urine contained only those steroids which do not require 17-hydroxylation in their biosynthesis. Aldosterone was not produced in the patient and the metabolic product of its immediate precursor, 18-hydroxy-11-dehydro-tetrahydrocorticosterone, was excreted in markedly elevated amounts. This apparent complete block in 18 oxidation was reversible upon long-term ACTH suppression within 27 days. Direct in vitro incubation of the patient's adrenal gland removed at operation demonstrated, 1) the complete lack of 17α-hydroxylase activity, 2) the functional block in the ability to oxidize the hydroxyl group at the 18 methyl side chain. The addition of physiological concentrations of angiotensin to the incubation medium further showed, 3) angiotensin mildly stimulated the entire aldosterone biosynthetic pathway, 4) angiotensin directly stimulated the conversion of 18-hydroxycorticosterone to aldosterone. We propose that in this patient, 17-hydroxylase deficiency produced a decreased plasma concentration of cortisol, followed by stimulation of deoxycorticosterone production by ACTH. The resultant increase in extracellular fluid volume suppressed plasma renin activity. This resulted in a low plasma concentration of angiotensin II which directly suppressed oxidation of 18-hydroxycorticosterone to aldosterone. This defect has been called corticosterone methyl oxidase defect type 2.

Design, Synthesis, and Pharmacokinetic Evaluation of O-Carbamoyl Tizoxanide Prodrugs

2020 ◽  
Vol 16 ◽  
Author(s):  
Xi He ◽  
Wenjun Hu ◽  
Fanhua Meng ◽  
Xingzhou Li
Keyword(s):  
Plasma Concentration ◽  
Broad Spectrum ◽  
Plasma Concentrations ◽  
Antiviral Drug ◽  
Systemic Exposure ◽  
Pharmacokinetic Profile ◽  
Hydroxyl Group ◽  
First Pass

Background: The broad-spectrum antiparasitic drug nitazoxanide (N) has been repositioned as a broad-spectrum antiviral drug. Nitazoxanide’s in vivo antiviral activities are mainly attributed to its metabolitetizoxanide, the deacetylation product of nitazoxanide. In reference to the pharmacokinetic profile of nitazoxanide, we proposed the hypotheses that the low plasma concentrations and the low system exposure of tizoxanide after dosing with nitazoxanide result from significant first pass effects in the liver. It was thought that this may be due to the unstable acyloxy bond of nitazoxanide. Objective: Tizoxanide prodrugs, with the more stable formamyl substituent attached to the hydroxyl group rather than the acetyl group of nitazoxanide, were designed with the thought that they might be more stable in plasma. It was anticipated that these prodrugs might be less affected by the first pass effect, which would improve plasma concentrations and system exposure of tizoxanide. Method: These O-carbamoyl tizoxanide prodrugs were synthesized and evaluated in a mouse model for pharmacokinetic (PK) properties and in an in vitro model for plasma stabilities. Results: The results indicated that the plasma concentration and the systemic exposure of tizoxanide (T) after oral administration of O-carbamoyl tizoxanide prodrugs were much greater than that produced by equimolar dosage of nitazoxanide. It was also found that the plasma concentration and the systemic exposure of tizoxanide glucuronide (TG) were much lower than that produced by nitazoxanide. Conclusion: Further analysis showed that the suitable plasma stability of O-carbamoyl tizoxanide prodrugs is the key factor in maximizing the plasma concentration and the systemic exposure of the active ingredient tizoxanide.

scholarly journals Hedgehog pathway permissive conditions allow generation of immortal cell lines from granule cells derived from cancerous and non-cancerous cerebellum

Open Biology ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 180145 ◽  
Author(s):  
Constantin Heil
Keyword(s):  
Cell Lines ◽  
Hedgehog Pathway ◽  
Simple Method ◽  
Genetic Ablation ◽  
Neural Lineage ◽  
Shh Pathway ◽  
Pathway Activation

Cerebellar granule cell progenitors (GCPs) undergo proliferation in the post-natal cerebellum that is dependent on sonic hedgehog (SHH) signalling. Deregulated SHH signalling leads to type 2 medulloblastoma (MB). In this work, a novel cell culture protocol is described, which is suitable for the establishment and long-term maintenance of GCP-derived cells. This method is first applied to SHH pathway active MB cells from Atoh1 -cre; Ptch1 FL/FL tumours, which leads to the generation of neurosphere-like cell lines expressing GCP markers and an active SHH signalling pathway. These cells also show high sensitivity to the Smoothened inhibitor vismodegib, therefore recapitulating the SHH pathway requirement for survival shown by type 2 MB. Analysis of culture supplements reveals that bFGF and fetal bovine serum act as inhibitors of the SHH pathway and therefore preclude generation of cell lines that are relevant to the study of the SHH pathway. Consequently, these insights are transferred from the context of MB to non-transformed, post-natal day 7 cerebellum-derived cellular explants. In contrast to other, previously used methods, these GCP cultures proliferate indefinitely and depend on SHH pathway activation, either by means of the small molecule SAG or through genetic ablation of Ptch1 . This culture method therefore leads to the generation of immortal neurosphere-like cell lines, that are named murine SAG-dependent spheres (mSS). Despite long-term culture, mSS cells remain dependent on continuous stimulation of the SHH pathway. Further, mSS cells maintain their lineage after extensive periods in vitro, as demonstrated by their differentiation towards the neural lineage. Herein a simple method for the generation of immortal cell lines from murine cerebella is defined. These lines can be maintained indefinitely through hedgehog pathway activation and maintain the GCP lineage.

scholarly journals A Genome-wide Association Study to Identify Candidate Genes for Metabolic Disorders in Offspring by in Vitro Fertilization

2022 ◽  
Author(s):  
Lihong Liu ◽  
Siyao HA ◽  
MingQing Li ◽  
Zhiling Li
Keyword(s):  
Lipid Metabolism ◽  
Health Risks ◽  
Genome Wide Association Study ◽  
Vitro Fertilization ◽  
Genome Wide ◽  
A Genome ◽  
Offspring Health

Abstract BackgroundIn vitro fertilization (IVF) processes increase offspring's short-term and long-term health risks, but their mechanisms remain unclear. MethodsWe conducted a bibliometric analysis to determine the landscape of IVF offspring health. Subsequently, a bioinformatics method was utilized to identify the co-genes properties and biological function mechanisms of IVF and type 2 diabetes mellitus (T2DM). Finally, we predicted compounds against key targets and performed multiple validations of the mechanisms underlying IVF offspring health risks. ResultsWe identified 15 genes associated with T2DM, and their biological functions are primarily associated with lipid metabolism. We also identified the properties of co-genes, modified characteristics, identified 3 SNPs sites, and determined the three core genes, APOA1, APOB, and APOE, which were mainly correlated with metabolic and cardiovascular diseases. In addition, we predicted drugs that may improve metabolic abnormalities in IVF offspring. ConclusionsThe impact of aberrant lipid metabolism in offspring after IVF therapy warrants additional investigation, particularly in terms of long-term health consequences and possible mechanisms.

scholarly journals Progesterone increases plasma volume independent of estradiol

2005 ◽  
Vol 98 (6) ◽  
pp. 1991-1997 ◽  
Author(s):  
Nina S. Stachenfeld ◽  
Hugh S. Taylor
Keyword(s):  
Plasma Concentration ◽  
Plasma Volume ◽  
Gnrh Antagonist ◽  
Water Movement ◽  
Extracellular Fluid ◽  
Plasma Renin ◽  
Escape Rate ◽  
Independent Effect ◽  
Transcapillary Escape Rate ◽  
Fluid Regulation

Adequate plasma volume (PV) and extracellular fluid (ECF) volume are essential for blood pressure and fluid regulation. We tested the hypotheses that combined progesterone (P4)-estrogen (E2) administration would increase ECF volume with proportional increases in PV, but that P4would have little independent effect on either PV or ECF volume. We further hypothesized that this P4-E2-induced fluid expansion would be a function of renin-angiotensin-aldosterone system stimulation. We suppressed P4and E2with a gonadotropin-releasing hormone (GnRH) antagonist in eight women (25 ± 2 yr) for 16 days; P4(200 mg/day) was added for days 5–16 (P4) and 17β-estradiol (2 × 0.1 mg/day patches) for days 13–16 (P4-E2). On days 2 (GnRH antagonist), 9 (P4), and 16 (P4-E2), we estimated ECF and PV. To determine the rate of protein and thus water movement across the ECF, we also measured transcapillary escape rate of albumin. In P4, [Formula: see text] increased from 2.5 ± 1.3 to 12.0 ± 2.8 ng/ml ( P < 0.05) with no change in [Formula: see text] (21.5 ± 9.4 to 8.6 ± 2.0 pg/ml). In P4-E2, plasma concentration of P4remained elevated (11.3 ± 2.7 ng/ml) and plasma concentration of E2increased to 254.1 ± 52.7 pg/ml ( P < 0.05). PV increased during P4(46.6 ± 2.5 ml/kg) and P4-E2(48.4 ± 3.9 ml/kg) compared with GnRH antagonist (43.3 ± 3.2 ml/kg; P < 0.05), as did ECF (206 ± 19, 244 ± 25, and 239 ± 27 ml/kg for GnRH antagonist, P4, and P4-E2, respectively; P < 0.05). Transcapillary escape rate of albumin was lowest during P4-E2(5.8 ± 1.3, 3.5 ± 1.7, and 2.2 ± 0.4%/h for GnRH antagonist, P4, and P4-E2, respectively; P < 0.05). Serum aldosterone increased during P4and P4-E2compared with GnRH antagonist (79 ± 17, 127 ± 13, and 171 ± 25 pg/ml for GnRH antagonist, P4, and P4-E2, respectively; P < 0.05), but plasma renin activity and plasma concentration of ANG II were only increased by P4-E2. This study is the first to isolate P4effects on ECF; however, the mechanisms for the ECF and PV expansion have not been clearly defined.

Evidence for paracrine/autocrine regulation of GLP-1-producing cells

2013 ◽  
Vol 305 (10) ◽  
pp. C1041-C1049 ◽  
Author(s):  
Camilla Kappe ◽  
Qimin Zhang ◽  
Jens J. Holst ◽  
Thomas Nyström ◽  
Åke Sjöholm
Keyword(s):  
Cell Viability ◽  
Insulin Signaling ◽  
Dipeptidyl Peptidase 4 ◽  
Beneficial Effects ◽  
Novel Drugs ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1), secreted from gut L cells upon nutrient intake, forms the basis for novel drugs against type 2 diabetes (T2D). Secretion of GLP-1 has been suggested to be impaired in T2D and in conditions associated with hyperlipidemia and insulin resistance. Further, recent studies support lipotoxicity of GLP-1-producing cells in vitro. However, little is known about the regulation of L-cell viability/function, the effects of insulin signaling, or the potential effects of stable GLP-1 analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors. We determined effects of insulin as well as possible autocrine action of GLP-1 on viability/apoptosis of GLP-1-secreting cells in the presence/absence of palmitate, while also assessing direct effects on function. The studies were performed using the GLP-1-secreting cell line GLUTag, and palmitate was used to simulate hyperlipidemia. Our results show that palmitate induced production of reactive oxygen species and caspase-3 activity and reduced cell viability are significantly attenuated by preincubation with insulin/exendin-4. The indicated lipoprotective effect of insulin/exendin-4 was not detectable in the presence of the GLP-1 receptor (GLP-1R) antagonist exendin (9–39) and attenuated in response to pharmacological inhibition of exchange protein activated by cAMP (Epac) signaling, while protein kinase A inhibition had no significant effect. Insulin/exendin-4 also significantly stimulate acute and long-term GLP-1 secretion in the presence of glucose, suggesting novel beneficial effects of insulin signaling and GLP-1R activation on glycemia through enhanced mass of GLP-1-producing cells and enhanced GLP-1 secretion. In addition, the effects of insulin indicate that not only is GLP-1 important for insulin secretion but altered insulin signaling may contribute to an altered GLP-1 secretion.

RISE IN PLASMA CONCENTRATION OF ALDOSTERONE DURING LONG-TERM ANGIOTENSIN II SUPPRESSION

1981 ◽  
Vol 91 (3) ◽  
pp. 457-465 ◽  
Author(s):  
J. STAESSEN ◽  
P. LIJNEN ◽  
R. FAGARD ◽  
L. J. VERSCHUEREN ◽  
A. AMERY
Keyword(s):  
Angiotensin Ii ◽  
Plasma Concentration ◽  
Enzyme Inhibitor ◽  
Plasma Renin ◽  
Hypotensive Effect ◽  
Angiotensin I ◽  
Angiotensin I Converting Enzyme ◽  
Plasma Angiotensin ◽  
Orally Active

The plasma concentration of aldosterone was followed in seven hypertensive patients before and during long-term angiotensin II suppression with the orally active angiotensin-I-converting-enzyme inhibitor, captopril. The plasma concentration of aldosterone decreased initially from 74 to 21 pg/ml (P < 0·05) after 1 month of administration of captopril. Thereafter the plasma concentration of aldosterone began to rise and after 1 year reached a level of 165 pg/ml. During long-term captopril therapy the plasma renin activity remained increased and the plasma angiotensin II concentration suppressed. The mechanism responsible for the late rise of the plasma concentration of aldosterone during long-term angiotensin II suppression with captopril remains to be elucidated. A sizeable and lasting hypotensive effect was observed in all patients.

The effects of hyperglycaemia on thrombin-activatable fibrinolysis inhibitor

2009 ◽  
Vol 102 (09) ◽  
pp. 460-468 ◽  
Author(s):  
Chantal J. N. Verkleij ◽  
Max Nieuwdorp ◽  
Victor E. A. Gerdes ◽  
Matthias Mörgelin ◽  
Joost C. M. Meijers ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Diseases ◽  
Healthy Volunteers ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Sds Page ◽  
Fibrinolysis Inhibitor

SummaryEpidemiological studies have shown a strong association between type 2 diabetes mellitus and cardiovascular diseases, and hypofibrinolysis may contribute to this phenomenon. The aim of this study was to determine the effect of hyperglycaemia on thrombin-activatable fibrinolysis inhibitor (TAFI). Hyperglycaemia was mimicked in vitro by incubation of TAFI with glyceraldehyde and in vivo by hyperglycaemic clamping of healthy volunteers. The effects of long-term hyperglycaemia in vivo on TAFI were investigated by comparing TAFI from poorly regulated and tightly regulated patients with type 2 diabetes. In vitro glycated TAFI showed an altered migration pattern on SDS-PAGE due to aggregation. Glycated TAFI showed decreased activity after activation by thrombin-thrombomodulin in a glyceraldehyde-dosedependent manner and a reduced anti-fibrinolytic potential. In vivo, no differences in TAFI parameters were found after hyper-glycaemic clamping of healthy volunteers and between tightly and poorly regulated patients with type 2 diabetes. Moreover, TAFI purified from poorly regulated and tightly regulated patients with type 2 diabetes migrated similarly on SDS-PAGE, indicating little or no glycation of the protein. Despite the deleterious effects of glycation of TAFI in vitro on its function, TAFI was neither affected by hyperglycaemic clamping, nor by long-term hyperglycaemia in patients with type 2 diabetes. This is in contrast to fibrinolytic factors as plasminogen-activator inhibitor I and tissue-type plasminogen activator, which are affected. We therefore hypothesise that a normally functioning TAFI under hyperglycaemic conditions may tip the haemostatic balance towards hypofibrinolysis, which may contribute to the development of cardiovascular diseases in type 2 diabetic patients.

scholarly journals Type 2 diabetes alters bone and marrow blood flow and vascular control mechanisms in the ZDF rat

2015 ◽  
Vol 225 (1) ◽  
pp. 47-58 ◽  
Author(s):  
John N Stabley ◽  
Rhonda D Prisby ◽  
Bradley J Behnke ◽  
Michael D Delp
Keyword(s):  
Type 2 Diabetes ◽  
Control Mechanisms ◽  
Vascular Control ◽  
Short Term ◽  
Nitric Oxide Synthase Inhibitor ◽  
Zdf Rats

Bone health and cardiovascular function are compromised in individuals with type 2 diabetes mellitus (T2DM). The purpose of this study was to determine whether skeletal vascular control mechanisms are altered during the progression of T2DM in Zucker diabetic fatty (ZDF) rats. Responses of the principal nutrient artery (PNA) of the femur from obese ZDF rats with prediabetes, short-term diabetes, and long-term diabetes to endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) vasodilation and potassium chloride, norepinephrine (NE), and a myogenic vasoconstrictor were determinedin vitro. Few changes in the PNA vasomotor responses occurred for the prediabetic and short-term diabetic conditions. Endothelium-dependent and -independent vasodilation were reduced, and NE and myogenic vasoconstriction were increased in obese ZDF rats with long-term diabetes relative to lean age-matched controls. Differences in endothelium-dependent vasodilation of the femoral PNA between ZDF rats and controls were abolished by the nitric oxide synthase inhibitorNG-nitro-l-arginine methyl ester. The passive pressure–diameter response of the femoral PNA was also lower across a range of intraluminal pressures with long-term T2DM. Regional bone and marrow perfusion and vascular conductance, measuredin vivousing radiolabeled microspheres, were lower in obese ZDF rats with long-term diabetes. These findings indicate that the profound impairment of the bone circulation may contribute to the osteopenia found to occur in long bones during chronic T2DM.

Relationship between Generation and Plasma Concentration of Anorganic Phosphorus. in Vivo Studies on Dialysis Patients and in Vitro Studies on Erythrocytes

1989 ◽  
Vol 12 (8) ◽  
pp. 524-532 ◽  
Author(s):  
H. Pogglitsch ◽  
W. Estelberger ◽  
W. Petek ◽  
S. Zitta ◽  
E. Ziak
Keyword(s):  
Renal Failure ◽  
Chronic Renal Failure ◽  
Plasma Concentration ◽  
Nonlinear Function ◽  
Extracellular Fluid ◽  
Red Cells ◽  
In Vitro Studies ◽  
In Vivo Studies

The plasma concentration of inorganic phosphorus (Pi) was determined before, during and after hemodialysis in 28 patients with chronic renal failure. Pi plasma concentration decreased rapidly when hemodialysis was started but did not fall below normal levels during continued dialysis. These changes of Pi concentration were fitted to a model of Pi kinetics in which Pi delivery to plasma is a nonlinear function of the extracellular Pi concentration. In separate in vitro studies, erythrocytes from six subjects with normal renal function and from 14 patients with chronic renal failure were incubated in homologous plasma with various amounts of Pi added. All other factors known to affect the Pi shift between intra - and extracellular fluid compartments (pH, calcium concentration) were kept constant. The relation between Pi concentration in plasma used for incubation and in red cells after 1h incubation suggested a mechanism in which a high plasma concentration results in movement of Pi into red cells where Pi is stored most probably in glucose esters. At low Pi plasma concentration Pi is delivered to plasma at a rate which cannot be explained solely by passive movement of intracellular Pi to plasma but requires additional generation from intracellular storage forms. The generation and delivery of Pi in patients and in their erythrocytes indicate a simple cell-mediated Pi homeostasis counter-acting abnormal fluctuations of plasma Pi.

Targeting α -(1,4)-Glucosidase in Diabetes Mellitus Type 2: The Role of New Synthetic Coumarins as Potent Inhibitors

2019 ◽  
Vol 18 (27) ◽  
pp. 2327-2337
Author(s):  
Catalina Figueroa-Benavides ◽  
Maria João Matos ◽  
Montserrat Peñaloza-Amion ◽  
Rubén Veas ◽  
Gabriela Valenzuela-Barra ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Diabetes Mellitus Type 2 ◽  
Hydrophobic Interactions ◽  
Docking Studies ◽  
Diabetes Mellitus Type ◽  
Glucosidase Inhibitors ◽  
Pharmacological Targets

Diabetes mellitus type 2 (DMT2) is a metabolic disease characterized by a chronic increase in glycemia that promotes several long-term complications and high mortality. Some enzymes involved in glycaemic control, such as α -(1,4)-glucosidase, have now been established as novel pharmacological targets. Coumarins have shown benefits in attenuating signs and complications of DMT2, including inhibition of this enzyme. In this work, new synthetic coumarins (bearing different amide and aryl substituents) were studied in vitro as inhibitors of α-(1,4)-glucosidase. Among them, five molecules proved to be excellent α-(1,4)-glucosidase inhibitors, being compound 7 (IC50 = 2.19 µM) about 200 times more potent than acarbose, a drug currently used for the treatment of DMT2. In addition, most of the coumarins presented uncompetitive inhibition for the α-(1,4)-glucosidase. Molecular docking studies revealed that coumarins bind to the active site of the enzyme in a more external area comparing to the substrate, without interfering with it, and displaying aromatic and hydrophobic interactions, as well as some hydrogen bonds. According to the results, aromatic interactions with two phenylalanine residues, 157 and 177, were the most common among the studied coumarins. This study is a step forward for the understanding of coumarins as potential anti-diabetic compounds displaying α-(1,4)-glucosidase inhibition.

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