scholarly journals Brain Alanine Formation as an Ammonia-Scavenging Pathway during Hyperammonemia: Effects of Glutamine Synthetase Inhibition in Rats and Astrocyte—Neuron Co-Cultures

2013 ◽  
Vol 33 (8) ◽  
pp. 1235-1241 ◽  
Author(s):  
Sherry Dadsetan ◽  
Eva Kukolj ◽  
Lasse K Bak ◽  
Michael SØrensen ◽  
Peter Ott ◽  
...  
Keyword(s):  
Hepatic Encephalopathy ◽  
Glutamine Synthetase ◽  
Drug Target ◽  
Methionine Sulfoximine ◽  
Concerted Action ◽  
N Incorporation ◽  
Dose Dependent ◽  
The Brain

Hyperammonemia is a major etiological toxic factor in the development of hepatic encephalopathy. Brain ammonia detoxification occurs primarily in astrocytes by glutamine synthetase (GS), and it has been proposed that elevated glutamine levels during hyperammonemia lead to astrocyte swelling and cerebral edema. However, ammonia may also be detoxified by the concerted action of glutamate dehydrogenase (GDH) and alanine aminotransferase (ALAT) leading to trapping of ammonia in alanine, which in vivo likely leaves the brain. Our aim was to investigate whether the GS inhibitor methionine sulfoximine (MSO) enhances incorporation of 15NH4+ in alanine during acute hyperammonemia. We observed a fourfold increased amount of 15NH4 incorporation in brain alanine in rats treated with MSO. Furthermore, co-cultures of neurons and astrocytes exposed to 15NH4Cl in the absence or presence of MSO demonstrated a dose-dependent incorporation of 15NH4 into alanine together with increased 15N incorporation in glutamate. These findings provide evidence that ammonia is detoxified by the concerted action of GDH and ALAT both in vivo and in vitro, a mechanism that is accelerated in the presence of MSO thereby reducing the glutamine level in brain. Thus, GS could be a potential drug target in the treatment of hyperammonemia in patients with hepatic encephalopathy.

scholarly journals The Antiviral Effect of Novel Steroidal Derivatives on Flaviviruses

2021 ◽  
Vol 12 ◽  
Author(s):  
Luping Zhang ◽  
Dengyuan Zhou ◽  
Qiuyan Li ◽  
Shuo Zhu ◽  
Muhammad Imran ◽  
...  
Keyword(s):  
Antiviral Effect ◽  
Therapeutic Drug ◽  
Dependent Manner ◽  
Design And Synthesis ◽  
Invasion Stage ◽  
Synthetic Derivatives ◽  
Dose Dependent ◽  
The Brain

Flaviviruses are the major emerging arthropod-borne pathogens globally. However, there is still no practical anti-flavivirus approach. Therefore, existing and emerging flaviviruses desperately need active broad-spectrum drugs. In the present study, the antiviral effect of steroidal dehydroepiandrosterone (DHEA) and 23 synthetic derivatives against flaviviruses such as Japanese encephalitis virus (JEV), Zika virus (ZIKV), and Dengue virus (DENV) were appraised by examining the characteristics of virus infection both in vitro and in vivo. Our results revealed that AV1003, AV1004 and AV1017 were the most potent inhibitors of flavivirus propagation in cells. They mainly suppress the viral infection in the post-invasion stage in a dose-dependent manner. Furthermore, orally administered compound AV1004 protected mice from lethal JEV infection by increasing the survival rate and reducing the viral load in the brain of infected mice. These results indicate that the compound AV1004 might be a potential therapeutic drug against JEV infection. These DHEA derivatives may provide lead scaffolds for further design and synthesis of potential anti-flavivirus potential drugs.

An engineeredE. coliNissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans

2019 ◽  
Vol 11 (475) ◽  
pp. eaau7975 ◽  
Author(s):  
Caroline B. Kurtz ◽  
Yves A. Millet ◽  
Marja K. Puurunen ◽  
Mylène Perreault ◽  
Mark R. Charbonneau ◽  
...  
Keyword(s):  
Hepatic Encephalopathy ◽  
Urea Cycle ◽  
Phase 1 ◽  
Negative Regulator ◽  
Urea Cycle Disorders ◽  
Healthy Humans ◽  
Cycle Disorders ◽  
Dose Dependent

The intestine is a major source of systemic ammonia (NH3); thus, capturing part of gut NH3may mitigate disease symptoms in conditions of hyperammonemia such as urea cycle disorders and hepatic encephalopathy. As an approach to the lowering of blood ammonia arising from the intestine, we engineered the orally delivered probioticEscherichia coliNissle 1917 to create strain SYNB1020 that converts NH3tol-arginine (l-arg). We up-regulated arginine biosynthesis in SYNB1020 by deleting a negative regulator ofl-arg biosynthesis and inserting a feedback-resistantl-arg biosynthetic enzyme. SYNB1020 producedl-arg and consumed NH3in an in vitro system. SYNB1020 reduced systemic hyperammonemia, improved survival in ornithine transcarbamylase–deficientspfashmice, and decreased hyperammonemia in the thioacetamide-induced liver injury mouse model. A phase 1 clinical study was conducted including 52 male and female healthy adult volunteers. SYNB1020 was well tolerated at daily doses of up to 1.5 × 1012colony-forming units administered for up to 14 days. A statistically significant dose-dependent increase in urinary nitrate, plasma15N-nitrate (highest dose versus placebo,P= 0.0015), and urinary15N-nitrate was demonstrated, indicating in vivo SYNB1020 activity. SYNB1020 concentrations reached steady state by the second day of dosing, and excreted cells were alive and metabolically active as evidenced by fecal arginine production in response to added ammonium chloride. SYNB1020 was no longer detectable in feces 2 weeks after the last dose. These results support further clinical development of SYNB1020 for hyperammonemia disorders including urea cycle disorders and hepatic encephalopathy.

scholarly journals Antifungal Activity of LY303366, a Novel Echinocandin B, in Experimental Disseminated Candidiasis in Rabbits

1999 ◽  
Vol 43 (9) ◽  
pp. 2148-2155 ◽  
Author(s):  
Ruta Petraitiene ◽  
Vidmantas Petraitis ◽  
Andreas H. Groll ◽  
Myrna Candelario ◽  
Tin Sein ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Vena Cava ◽  
Study Groups ◽  
Disseminated Candidiasis ◽  
Echinocandin B ◽  
Time Kill ◽  
Dose Dependent ◽  
The Brain

ABSTRACT The safety and antifungal activity of LY303366 (LY), a new broad-spectrum semisynthetic echinocandin, were studied against disseminated candidiasis in persistently neutropenic rabbits. In vitro time-kill assays demonstrated that LY has concentration-dependent fungicidal activity. The pharmacokinetics of LY in the plasma of nonneutropenic rabbits suggested a linear relationship between dose and area under the curve (AUC). The times spent above the MIC during the experimental dosing interval of 24 h were 4 h for LY at 0.1 mg/kg of body weight/day (LY0.1), 8 h for LY at 0.25 mg/kg/day (LY0.25), 12 h for LY at 0.5 mg/kg/day (LY0.5), and 20 h for LY at 1 mg/kg/day (LY1). Antifungal therapy was administered to infected rabbits for 10 days starting 24 h after the intravenous (i.v.) inoculation of 103 Candida albicansblastoconidia. Study groups consisted of untreated controls (UCs) and animals treated with amphotericin B (AmB; 1 mg/kg/day i.v.), fluconazole (FLU; 10 mg/kg/day i.v.), and LY0.1, LY0.25, LY0.5, or LY1 i.v. Rabbits treated with LY0.5, LY1, AmB, and FLU had similarly significant clearance of C. albicans from the liver, spleen, kidney, lung, vena cava, and brain in comparison to that for UCs. There was a dose-dependent clearance of C. albicansfrom tissues in response to LY. Among rabbits treated with LY0.1 there was a significant reduction of C. albicans only in the spleen. In animals treated with LY0.25 there was a significant reduction in all tissues but the brain. By comparison, LY0.5 and LY1 cleared all tissues, including the brain, of C. albicans. These in vivo findings were consistent with the results of in vitro time-kill assays. A dose-dependent effect of altered cell wall morphology was observed among UCs and animals treated with LY0.1, and LY0.25, with a progressive transition from hyphal structure to disrupted yeast forms. Serum creatinine levels were higher and serum potassium levels were lower in AmB-treated rabbits than in UCs and LY- and FLU-treated rabbits. LY0.5 and LY1 were well tolerated, displayed predictable pharmacokinetics in plasma, and had activities comparable to those of AmB and FLU in the treatment of disseminated candidiasis in persistently neutropenic rabbits.

Anticonvulsant properties of amino-oxyacetic acid

1961 ◽  
Vol 201 (5) ◽  
pp. 833-837 ◽  
Author(s):  
J. P. Da Vanzo ◽  
M. E. Greig ◽  
M. A. Cronin
Keyword(s):  
Anticonvulsant Activity ◽  
Aminobutyric Acid ◽  
Methionine Sulfoximine ◽  
Pentobarbital Sodium ◽  
The Brain ◽  
Fasted Rats ◽  
Optimal Protection ◽  
Oxyacetic Acid

Amino-oxyacetic acid (AOAA), a compound which inhibits γ-aminobutyric-α-ketoglutaric transaminase in vitro and causes accumulations of γ-aminobutyric acid (GABA) in vivo, has anticonvulsant activity against convulsions caused by thiosemicarbazide in rats, mice, and cats and against methionine sulfoximine convulsions in cats. Pentobarbital sodium and trimethadione were slightly active in protecting against thiosemicarbazide-induced convulsions whereas chlorpromazine and methadone were inactive. Pyridoxal, ethanol (in fasted rats), and paraldehyde showed anticonvulsant activity in thiosemicarbazide convulsions. The anticonvulsant activity of AOAA did not appear to be due to increased GABA levels in the brain for the following reasons: a) maximum GABA levels occurred 6–8 hr after administration of AOAA. Optimal protection against thiosemicarbazide, however, was afforded during the first 3 hr after administration and it had fallen off markedly at 6 hr. b) Hydroxylamine, which has been reported to raise GABA levels, had no anticonvulsant activity on thiosemicarbazide.

Effect of pH and inhibitors on beta-amyloid fibril assembly

1996 ◽  
Vol 54 ◽  
pp. 752-753
Author(s):  
Beverly E. Maleeff ◽  
Timothy K. Hart ◽  
Stephen J. Wood ◽  
Ronald Wetzel
Keyword(s):  
Amyloid Fibril ◽  
Peptide Fragment ◽  
Hydrophobic Peptides ◽  
Amyloid Fibril Formation ◽  
Effects Of Ph ◽  
Severity Of The Disease ◽  
Kinetics Of ◽  
The Brain

Alzheimer's disease is characterized post-mortem in part by abnormal extracellular neuritic plaques found in brain tissue. There appears to be a correlation between the severity of Alzheimer's dementia in vivo and the number of plaques found in particular areas of the brain. These plaques are known to be the deposition sites of fibrils of the protein β-amyloid. It is thought that if the assembly of these plaques could be inhibited, the severity of the disease would be decreased. The peptide fragment Aβ, a precursor of the p-amyloid protein, has a 40 amino acid sequence, and has been shown to be toxic to neuronal cells in culture after an aging process of several days. This toxicity corresponds to the kinetics of in vitro amyloid fibril formation. In this study, we report the biochemical and ultrastructural effects of pH and the inhibitory agent hexadecyl-N-methylpiperidinium (HMP) bromide, one of a class of ionic micellar detergents known to be capable of solubilizing hydrophobic peptides, on the in vitro assembly of the peptide fragment Aβ.

Soluble Thrombomodulin Purified from Human Urine Exhibits a Potent Anticoagulant Effect In Vitro and In Vivo

1995 ◽  
Vol 73 (05) ◽  
pp. 805-811 ◽  
Author(s):  
Yasuo Takahashi ◽  
Yoshitaka Hosaka ◽  
Hiromi Niina ◽  
Katsuaki Nagasawa ◽  
Masaaki Naotsuka ◽  
...  
Keyword(s):  
Human Urine ◽  
Specific Activity ◽  
Anticoagulant Activity ◽  
Rabbit Lung ◽  
Soluble Thrombomodulin ◽  
Molecular Weights ◽  
Dose Dependent Fashion ◽  
Dose Dependent

SummaryWe examined the anticoagulant activity of two major molecules of soluble thrombomodulin purified from human urine. The apparent molecular weights of these urinary thrombomodulins (UTMs) were 72,000 and 79,000, respectively. Both UTMs showed more potent cofactor activity for protein C activation [specific activity >5,000 thrombomodulin units (TMU)/mg] than human placental thrombomodulin (2,180 TMU/mg) and rabbit lung thrombomodulin (1,980 TMU/mg). The UTMs prolonged thrombin-induced fibrinogen clotting time (>1 TMU/ml), APTT (>5 TMU/ml), TT (>5 TMU/ml) and PT (>40 TMU/ml) in a dose-dependent fashion. These effects appeared in the concentration range of soluble thrombomodulins present in human plasma and urine. In the rat DIC model induced by thromboplastin, administration of UTMs by infusion (300-3,000 TMU/kg) restored the hematological abnormalities derived from DIC in a dose-dependent fashion. These results demonstrate that UTMs exhibit potent anticoagulant and antithrombotic activities, and could play a physiologically important role in microcirculation.

Novel Phospholipid-Based Labrasol Nanomicelles Loaded Flavonoids for Oral Delivery with Enhanced Penetration and Anti-Brain Tumor Efficiency

2020 ◽  
Vol 17 (3) ◽  
pp. 229-245
Author(s):  
Gang Wang ◽  
Junjie Wang ◽  
Rui Guan
Keyword(s):  
Drug Delivery ◽  
Brain Tumor ◽  
Oral Delivery ◽  
Safe Delivery ◽  
Drug Delivery Vehicles ◽  
Therapeutic Benefits ◽  
Delivery Vehicles ◽  
The Brain

Background: Owing to the rich anticancer properties of flavonoids, there is a need for their incorporation into drug delivery vehicles like nanomicelles for safe delivery of the drug into the brain tumor microenvironment. Objective: This study, therefore, aimed to prepare the phospholipid-based Labrasol/Pluronic F68 modified nano micelles loaded with flavonoids (Nano-flavonoids) for the delivery of the drug to the target brain tumor. Methods: Myricetin, quercetin and fisetin were selected as the initial drugs to evaluate the biodistribution and acute toxicity of the drug delivery vehicles in rats with implanted C6 glioma tumors after oral administration, while the uptake, retention, release in human intestinal Caco-2 cells and the effect on the brain endothelial barrier were investigated in Human Brain Microvascular Endothelial Cells (HBMECs). Results: The results demonstrated that nano-flavonoids loaded with myricetin showed more evenly distributed targeting tissues and enhanced anti-tumor efficiency in vivo without significant cytotoxicity to Caco-2 cells and alteration in the Trans Epithelial Electric Resistance (TEER). There was no pathological evidence of renal, hepatic or other organs dysfunction after the administration of nanoflavonoids, which showed no significant influence on cytotoxicity to Caco-2 cells. Conclusion: In conclusion, Labrasol/F68-NMs loaded with MYR and quercetin could enhance antiglioma effect in vitro and in vivo, which may be better tools for medical therapy, while the pharmacokinetics and pharmacodynamics of nano-flavonoids may ensure optimal therapeutic benefits.

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