scholarly journals The catabolism of intravenously injected heparan N-[35S]sulphate in the rat

1977 ◽  
Vol 166 (3) ◽  
pp. 373-379 ◽  
Author(s):  
Martin A. Perry ◽  
Gillian M. Powell ◽  
Frederick S. Wusteman ◽  
C. Gerald Curtis
Keyword(s):  
Heparan Sulphate ◽  
The Body ◽  
Whole Body ◽  
General Distribution ◽  
In Vitro Experiments ◽  
Metabolic Fate ◽  
Inorganic Sulphate ◽  
Anaesthetized Rats

The metabolic fate of heparan N-[35S]sulphate was studied in rats. Heparan sulphate was obtained from either bovine aorta or lung and labelled with 35S by desulphation and subsequent resulphation in vitro. Experiments in which heparan N-[35S]sulphate was administered intravenously to either free-range or wholly anaesthetized rats with ureter cannulae established that substantial desulphation occurs in vivo, with elimination of inorganic [35S]sulphate in urine. Oligosaccharides labelled with 35S, possible intermediates in heparan sulphate degradation, could not be detected in urine or blood. The general distribution of radioactivity after administration of heparan N-[35S]sulphate, as demonstrated by whole-body radioautography, suggested that desulphation was not restricted to one organ in particular. Support for this view was obtained in experiments in which heparan N-[35S]sulphate was administered to animals after the removal of kidneys, liver, spleen, pancreas or gastrointestinal tract. In all cases inorganic [35S]sulphate was still produced. The ability of rats of desulphate heparan N-[35S]sulphate was progressively impaired by increasing concentrations of heparin administered simultaneously. It was concluded that heparan sulphate is metabolized at a number of sites in the body by a sequence of degradative events leading to the formation of inorganic sulphate. It is also concluded that at least some of these events are common to heparan sulphate and heparin.

High Resolution NMR Spectroscopy on Whole-Body Imagers:Optimized Single-and Multi-Pulse Experiments in Vitro

1995 ◽  
Vol 50 (10) ◽  
pp. 942-948
Author(s):  
Fritz Schick
Keyword(s):  
Aqueous Solutions ◽  
Spin Echo ◽  
Single Pulse ◽  
Spin Systems ◽  
The Body ◽  
Coupling Constants ◽  
Whole Body ◽  
Receiver Coil

Abstract From 100 ml spherical glass bottles filled with aqueous solutions and suspended in a homogeneous magnetic field, NMR spectra with linewidths of about 0.7 Hz were achieved in single-pulse and multi-pulse spectra. A relatively wide receiver coil as the body coil or the standard head coil of the manufacturer were employed to acquire spectra after different non-localized pulse sequences. Examples of single-pulse spectra and double spin-echo spectra of aqueous solutions with lactate, citrate, or glucose are demonstrated and discussed. The fact that all experiments can be performed using well-defined pulse angles acting on the entire sample at the field strenght of the whole-body unit allows to determine the characteristics (e.g. chemical shift differences, coupling constants) of spin systems of biologically important molecules precisely, without need for additional spectrometers. Constant flip angles are advantageous for adequate theoretical analysis of spectra from coupled spin systems. The effects of a defined "misadjustment" of the transmitter on the spectra can be measured directly, whereas localized methods always yield a superposition of signals due to the distribution of flip angles inside the selected volume. In some cases, optimized sequence parameters for localized examinations in vivo can be derived numerically from the analyzed coupling data.

scholarly journals Tracing Metabolic Fate of Mitochondrial Glycine Cleavage System Derived Formate In Vitro and In Vivo

2020 ◽  
Vol 21 (22) ◽  
pp. 8808
Author(s):  
Yee-Ling Tan ◽  
Nga-Lai Sou ◽  
Feng-Yao Tang ◽  
Hsin-An Ko ◽  
Wei-Ting Yeh ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Hepatoma Cell ◽  
Model Systems ◽  
Whole Body ◽  
Co2 Production ◽  
Glycine Cleavage System ◽  
Metabolic Fate ◽  
Glycine Cleavage

Folate-mediated one-carbon (1C) metabolism is a major target of many therapies in human diseases. Studies have focused on the metabolism of serine 3-carbon as it serves as a major source for 1C units. The serine 3-carbon enters the mitochondria transferred by folate cofactors and eventually converted to formate and serves as a major building block for cytosolic 1C metabolism. Abnormal glycine metabolism has been reported in many human pathological conditions. The mitochondrial glycine cleavage system (GCS) catalyzes glycine degradation to CO2 and ammonium, while tetrahydrofolate (THF) is converted into 5,10-methylene-THF. GCS accounts for a substantial proportion of whole-body glycine flux in humans, yet the particular metabolic route of glycine 2-carbon recycled from GCS during mitochondria glycine decarboxylation in hepatic or bone marrow 1C metabolism is not fully investigated, due to the limited accessibility of human tissues. Labeled glycine at 2-carbon was given to humans and primary cells in previous studies for investigating its incorporations into purines, its interconversion with serine, or the CO2 production in the mitochondria. Less is known on the metabolic fate of the glycine 2-carbon recycled from the GCS; hence, a model system tracing its metabolic fate would help in this regard. We took the direct approach of isotopic labeling to further explore the in vitro and in vivo metabolic fate of the 2-carbon from [2-13C]glycine and [2-13C]serine. As the 2-carbon of glycine and serine is decarboxylated and catabolized via the GCS, the original 13C-labeled 2-carbon is transferred to THF and yield methyleneTHF in the mitochondria. In human hepatoma cell-lines, 2-carbon from glycine was found to be incorporated into deoxythymidine (dTMP, dT + 1), M + 3 species of purines (deoxyadenine, dA and deoxyguanine, dG), and methionine (Met + 1). In healthy mice, incorporation of GCS-derived formate from glycine 2-carbon was found in serine (Ser + 2 via cytosolic serine hydroxy methyl transferase), methionine, dTMP, and methylcytosine (mC + 1) in bone marrow DNA. In these experiments, labeled glycine 2-carbon directly incorporates into Ser + 1, A + 2, and G + 2 (at C2 and C8 of purine) in the cytosol. It is noteworthy that since the serine 3-carbon is unlabeled in these experiments, the isotopic enrichments in dT + 1, Ser + 2, dA + 3, dG + 3, and Met + 1 solely come from the 2-carbon of glycine/serine recycled from GCS, re-enters the cytosolic 1C metabolism as formate, and then being used for cytosolic syntheses of serine, dTMP, purine (M + 3) and methionine. Taken together, we established model systems and successfully traced the metabolic fate of mitochondrial GCS-derived formate from glycine 2-carbon in vitro and in vivo. Nutritional supply significantly alters formate generation from GCS. More GCS-derived formate was used in hepatic serine and methionine syntheses, whereas more GCS-derived formate was used in dTMP synthesis in the bone marrow, indicating that the utilization and partitioning of GCS-derived 1C unit are tissue-specific. These approaches enable better understanding concerning the utilization of 1C moiety generated from mitochondrial GCS that can help to further elucidate the role of GCS in human disease development and progression in future applications. More studies on GCS using these approaches are underway.

scholarly journals Tetrodotoxin/Saxitoxins Selectivity of the Euryhaline Freshwater Pufferfish Dichotomyctere fluviatilis

Toxins ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 731
Author(s):  
Hongchen Zhu ◽  
Towa Sakai ◽  
Yuji Nagashima ◽  
Hiroyuki Doi ◽  
Tomohiro Takatani ◽  
...  
Keyword(s):  
The Body ◽  
Skin Tissue ◽  
Takifugu Rubripes ◽  
In Vitro Experiments ◽  
Long Period ◽  
In Vivo Experiment ◽  
The Given ◽  
Over Time

The present study evaluated differences in the tetrodotoxin (TTX)/saxitoxins (STXs) selectivity between marine and freshwater pufferfish by performing in vivo and in vitro experiments. In the in vivo experiment, artificially reared nontoxic euryhaline freshwater pufferfish Dichotomyctere fluviatilis were intrarectally administered a mixture of TTX (24 nmol/fish) and STX (20 nmol/fish). The amount of toxin in the intestine, liver, muscle, gonads, and skin was quantified at 24, 48, and 72 h. STX was detected in the intestine over a long period of time, with some (2.7–6.1% of the given dose) being absorbed into the body and temporarily located in the liver. Very little TTX was retained in the body. In the in vitro experiments, slices of the intestine, liver, and skin tissue prepared from artificially reared nontoxic D. fluviatilis and the marine pufferfish Takifugu rubripes were incubated in buffer containing TTX and STXs (20 nmol/mL each) for up to 24 or 72 h, and the amount of toxin taken up in the tissue was quantified over time. In contrast to T. rubripes, the intestine, liver, and skin tissues of D. fluviatilis selectively took up only STXs. These findings indicate that the TTX/STXs selectivity differs between freshwater and marine pufferfish.

scholarly journals The In Vivo and In Vitro Toxicokinetics of Citreoviridin Extracted from Penicillium citreonigrum

Toxins ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 360 ◽  
Author(s):  
Yosuke Uchiyama ◽  
Masahiko Takino ◽  
Michiko Noguchi ◽  
Nozomi Shiratori ◽  
Naoki Kobayashi ◽  
...  
Keyword(s):  
Permeability Coefficient ◽  
The Body ◽  
In Vitro Experiments ◽  
High Permeability ◽  
In Vivo Experiments ◽  
Permeability Study ◽  
High Bioavailability ◽  
S9 Fraction

Citreoviridin (CTVD), a mycotoxin called yellow rice toxin, is reported to be related to acute cardiac beriberi; however, its toxicokinetics remain unclear. The present study elucidated the toxicokinetics through in vivo experiments in swine and predicted the human toxicokinetics by comparing the findings to those from in vitro experiments. In vivo experiments revealed the high bioavailability of CTVD (116.4%) in swine. An intestinal permeability study using Caco-2 cells to estimate the toxicokinetics in humans showed that CTVD has a high permeability coefficient. When CTVD was incubated with hepatic S9 fraction from swine and humans, hydroxylation and methylation, desaturation, and dihydroxylation derivatives were produced as the predominant metabolites. The levels of these products produced using human S9 were higher than those obtained swine S9, while CTVD glucuronide was produced slowly in human S9 in comparison to swine S9. Furthermore, the elimination of CTVD by human S9 was significantly more rapid in comparison to that by swine S9. These results suggest that CTVD is easily absorbed in swine and that it remains in the body where it is slowly metabolized. In contrast, the absorption of CTVD in humans would be the same as that in swine, although its elimination would be faster.

In vivo n.m.r. imaging in medicine: the Aberdeen approach, both physical and biological

1980 ◽  
Vol 289 (1037) ◽  
pp. 519-533 ◽  
Keyword(s):  
Pulse Sequence ◽  
The Body ◽  
Spin Lattice Relaxation ◽  
Surrounding Tissue ◽  
Whole Body ◽  
Spin Concentration ◽  
Stage Of Development ◽  
Wide Range

A novel magnetic field and radio frequency (1.7 MHz) pulse sequence is described for a whole body n.m.r. imaging machine under construction. Selective excitation is used to obtain signals from successive lines of proton spins (water) across the body to build up an image of a transverse section. The images display spin concentration and spin-lattice relaxation time, T 1 , separately. For a 50 % change in T 1 to be discerned in the human trunk, a spatial resolution of 2 cm 3 is expected for a 2 min scan and 0.5 cm 3 for a 30 min scan. Very preliminary images at the present incomplete stage of development show the geometrical accuracy and T 1 discrimination: an in vivo image demonstrates some of the difficulties to be overcome. In vitro measurements of normal rabbit tissue samples have been made at 24 MHz to map the T 1 distributions that can be expected from normal subjects. The transposition of this information from rabbit to man, and from 24 MHz to 2.5 MHz have been checked and the comparison shown to be meaningful. Of pathological samples, human breast tumour and human liver metastases offer a good contrast to their surrounding tissue, and an experimental investigation has shown that tissue immediately surrounding a tumour also has an elevated T 1 value. A wide range of abnormalities that are associated with abnormal fluid formation in the body may be amenable to imaging by the n.m.r. technique. Potential hazards are believed to be small in the present generation of equipment.

Leptin and Gaba Interactions on Thermoregulation of Rats

2014 ◽  
Vol 7 (1) ◽  
pp. 20-24 ◽  
Author(s):  
Krassimira S. Yakimova ◽  
Rumen P. Nikolov ◽  
Ivan G. Todorov ◽  
Milen H. Hristov
Keyword(s):  
Body Temperature ◽  
Core Body Temperature ◽  
Point Of View ◽  
The Body ◽  
In Vitro Experiments ◽  
In Vivo Experiments ◽  
Male Wistar Rats ◽  
In Vivo Effects

Abstract Leptin inhibits feeding, reduces body weight and increases thermogenesis. Experimental data suggest involvement of GABAergic mechanisms in the regulation of feeding behavior and energy balance. The present study was set to determine the effect of combinations from leptin, GABAB-agonist baclofen and GABAB-antagonist CGP35348 on thermoregulation of male Wistar rats, using in vivo and in vitro experiments. The substances used for in vivo experiments were administered intraperitoneally (i.p.). The measurement of the body temperature was done via thermistor probes (TX8) and monitored on multichannel recorder Iso-Thermex16. In vitro experiments were conducted on rat PO/AH neurons, recorded extracellulary by conventional electrophysiological equipment, using brain slice preparations. The separate intraperitoneal injection of leptin as well as GABAB-antagonist CGP35348 produced significant hyperthermia in rats while the GABAB-agonist baclofen caused a decrease in the core body temperature. The probable synergy between the hyperthermic effects of leptin and GABAB-antagonist did not occur. On the contrary, the effect of this combination was lower as compared to the result of the separate administration of GABAB-antagonist. When leptin was applied just prior to GABAB-agonist baclofen, neither of their separate effects appeared. In vivo effects determined correlated with in vitro changes of firing rate observed in PO/AH neurons. The data from this study provide a new point of view concerning the interactions of leptin and GABA on the level of thermoregulation. These results represent a step forward in understanding the complicated mechanisms involved in thermoregulation.

scholarly journals Evaluation of Aminopolycarboxylate Chelators for Whole-Body Clearance of Free 225Ac: A Feasibility Study to Reduce Unexpected Radiation Exposure during Targeted Alpha Therapy

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1706
Author(s):  
Mitsuyoshi Yoshimoto ◽  
Yukie Yoshii ◽  
Hiroki Matsumoto ◽  
Mitsuhiro Shinada ◽  
Masashi Takahashi ◽  
...  
Keyword(s):  
Radiation Exposure ◽  
Feasibility Study ◽  
The Body ◽  
Whole Body ◽  
Targeted Alpha Therapy ◽  
Carboxylic Groups ◽  
Alpha Therapy ◽  
Body Clearance

Actinium-225 (225Ac) is a promising radionuclide used in targeted alpha therapy (TAT). Although 225Ac labeling of bifunctional chelating ligands is effective, previous in vivo studies reported that free 225Ac can be released from the drugs and that such free 225Ac is predominantly accumulated in the liver and could cause unexpected toxicity. To accelerate the clinical development of 225Ac TAT with a variety of drugs, preparing methods to deal with any unexpected toxicity would be valuable. The aim of this study was to evaluate the feasibility of various chelators for reducing and excreting free 225Ac and compare their chemical structures. Nine candidate chelators (D-penicillamine, dimercaprol, Ca-DTPA, Ca-EDTA, CyDTA, GEDTA TTHA, Ca-TTHA, and DO3A) were evaluated in vitro and in vivo. The biodistribution and dosimetry of free 225Ac were examined in mice before an in vivo chelating study. The liver exhibited pronounced 225Ac uptake, with an estimated human absorbed dose of 4.76 SvRBE5/MBq. Aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, significantly reduced 225Ac retention in the liver (22% and 30%, respectively). Significant 225Ac reductions were observed in the heart and remainder of the body with both Ca-DTPA and Ca-TTHA, and in the lung, kidney, and spleen with Ca-TTHA. In vitro interaction analysis supported the in vivo reduction ability of Ca-DTPA and Ca-TTHA. In conclusion, aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, were effective for whole-body clearance of free 225Ac. This feasibility study provides useful information for reducing undesirable radiation exposure from free 225Ac.

scholarly journals Aminopolycarboxylate Chelators Are Effective for Whole-body Clearance of Free 225ac: A Method to Reduce Unexpected Radiation Exposure During Targeted Alpha Therapy

2021 ◽  
Author(s):  
Mitsuyoshi Yoshimoto ◽  
Yukie Yoshii ◽  
Hiroki Matsumoto ◽  
Mitsuhiro Shinada ◽  
Masashi Takahashi ◽  
...  
Keyword(s):  
Radiation Exposure ◽  
The Body ◽  
Whole Body ◽  
Targeted Alpha Therapy ◽  
Carboxylic Groups ◽  
In Vitro Interaction ◽  
Alpha Therapy ◽  
Body Clearance

Abstract Purpose: Actinium-225 (225Ac) is a promising radionuclide used in targeted alpha therapy (TAT). Although 225Ac labelling of bifunctional chelating ligands is effective, previous in vivo studies have reported that free 225Ac can be released from the drugs. Notably, such free 225Ac predominantly accumulates in the liver and can cause unexpected toxicity. To accelerate the clinical development of 225Ac TAT, methods for addressing unexpected toxicity are therefore needed. In this study, we evaluated various chelators in vitro and in vivo with regard to reducing and excreting free 225Ac and compared their chemical structures. Methods: Nine candidate chelators (D-penicillamine, dimercaprol, Ca-DTPA, Ca-EDTA, CyDTA, GEDTA TTHA, Ca-TTHA, and DO3A) were tested. In vitro interaction of 225Ac and chelators was investigated. Biodistribution and dosimetry of free 225Ac were examined in mice prior to the in vivo chelating study. For in vivo chelation, nine candidate chelators were administered 1 h after free 225Ac injection, and biodistribution was compared 4 h after 225Ac injection in mice. Two favourable chelators were then investigated intensively for biodistribution 24 h after the 225Ac injection.Results: The liver exhibited pronounced 225Ac uptake corresponding to an estimated human absorbed dose of 4.76 SvRBE5/MBq. Aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, significantly reduced 225Ac retention in the liver (22% and 30%, respectively). Significant 225Ac reductions were observed in the heart and the remainder of the body with both Ca-DTPA and Ca-TTHA, and in the lung, kidney, and spleen for Ca-TTHA. In vitro interaction analysis supported the in vivo reduction ability of Ca-DTPA and Ca-TTHA.Conclusions. Aminopolycarboxylate chelators with five and six carboxylic groups, Ca-DTPA and Ca-TTHA, were effective for whole-body clearance of free 225Ac, with a significant reduction in the liver. This method could reduce undesirable radiation exposure from free 225Ac during 225Ac TAT.

scholarly journals Atomically precise silver clusterzymes protect mice from radiation damages

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jiao Guo ◽  
Haiyu Yang ◽  
Ya Liu ◽  
Wei Liu ◽  
Ruiying Zhao ◽  
...  
Keyword(s):  
Cell Viability ◽  
High Efficiency ◽  
Disease Diagnosis ◽  
The Body ◽  
Water Soluble ◽  
Whole Body ◽  
Dna Damages ◽  
Γ Ray

Abstract Background As we know, radiotherapy plays an irreplaceable role in the clinical management on solid tumors. However, due to the non-specific killing effects of ionizing radiation, normal tissues damages would be almost simultaneous inevitably. Therefore, ideal radioprotective agents with high efficiency and low toxicity are always desirable. In this work, atomically precise Ag14 clusterzymes were developed, and their applications in radioprotection were studied in vitro and in vivo for the first time. Methods The ultra-small glutathione supported Ag14 clusterzymes were synthesized by convenient sodium borohydride (NaBH4) reduction of thiolate-Ag (I) complexes and then they were purified by desalting columns. The enzyme-like activity and antioxidant capacity of Ag14 clusterzymes have been tested by various commercial kits, salicylic acid method and electron spin resonance (ESR). Next, they were incubated with L929 cells to evaluate whether they could increase cell viability after γ-ray irradiation. And then Ag14 clusterzymes were intravenously injected into C57 mice before 7 Gy whole-body γ-ray irradiation to evaluate the radioprotection effects in vivo. At last, the in vivo toxicities of Ag14 clusterzymes were evaluated through biodistribution test, hematological details, serum biochemical indexes and histological test in female Balb/c mice with intravenous injection of Ag14 clusterzymes. Results Our studies suggested atomically precise Ag14 clusterzymes were potential radioprotectants. Ag14 clusterzymes exhibited unique superoxide dismutase (SOD)-like activity, strong anti-oxidative abilities, especially on •OH scavenging. The Ag14 clusterzymes could effectively improve cell viability through eliminating ROS and prevent DNA damages in cells dealt with γ-ray irradiation. In vivo experiments showed that Ag14 clusterzymes could improve the irradiated mice survival rate by protecting hematological systems and repairing tissue oxidative stress damage generated by γ-ray irradiation. In addition, bio-distribution and toxicological experiments demonstrated that the ultrasmall Ag14 clusterzymes could be excreted quickly from the body by renal clearance and negligible toxicological responses were observed in mice up to 30 days. Conclusion In summary, atomically precise, ultrasmall and water soluble Ag14 clusterzymes with SOD-like activity were successfully developed and proved to be effective both in vitro and in vivo for radioprotection. Furthermore, with atomically precise molecular structure, Ag14 clusterzymes, on aspect of the catalytic and optical properties, may be improved by structure optimization on atom-scale level for other applications in disease diagnosis and treatment. Graphical Abstract

Octadentate catecholamide ligands for Pu(IV) based on linear or preorganized molecular backbones

1996 ◽  
Vol 15 (4) ◽  
pp. 352-360 ◽  
Author(s):  
PW Durbin ◽  
B. Kullgren ◽  
N. Jeung ◽  
J. Xu ◽  
SJ Rodgers ◽  
...  
Keyword(s):  
Metal Binding ◽  
Intraperitoneal Injection ◽  
Equimolar Amount ◽  
The Body ◽  
Whole Body ◽  
Great Stability ◽  
Gastric Intubation ◽  
Octadentate Ligand

Nine new octadentate ligands based on cyclic, spermine (3,4,3-LI), desferrioxamine (DFO), or H-shaped tetrakis amine (penten) molecular backbones were prepared containing catecholamide (CAM), carboxycatecholamide (CAM(C)), or terephthalamide (TAM) chelating units. Mice were injected intravenously with 238Pu(IV) citrate, treated with 30 μmol kg-1 of a ligand by intraperitoneal injection at 1 h or by gastric intubation at 3 min, and Pu retention in tissues and Pu transfer to excreta were measured at 24 h. Given by injection, three soluble ligands composed of MeTAM (3,4,3-LIMeTAM, DFO-MeTAM, H(2,2)-MeTAM) reduced Pu retention in the body to 27- 28% of control compared with 32 and 37% of control obtained in mice similarly treated with 3,4,3-LICAM(C) or CaNa3-DTPA, respectively. The MeTAM ligands reduced Pu retention in the skeleton as much as an equimolar amount of CaNa 3-DTPA, while Pu retention in the liver (on average, 16% of control) was significantly less than was obtained with CaNa3-DTPA (35% of control). Given orally, H(2,2)-MeTAM reduced Pu retention in the whole body to 58% of control compared with reductions to 62 and 94% of control achieved with 3,4,3-LICAM(C) or CaNa3-DTPA, respectively. Penten is both partially preorganized for metal binding and spatially suitable for encapsulation of actinide(IV), and ligands with the penten backbone are easier and less costly to prepare than those based on spermine or DFO. The biological results confirmed that penten is a suitable as well as practical structural backbone for new octadentate ligands. In agreement with the great stability of the ferric complex with MeTAM, as determined in vitro, the small, simple, soluble penten- based octadentate ligand, H(2,2)-MeTAM, was shown to be, overall, the most effective catecholamide ligand for enhancing Pu excretion. Either combined in H(2,2)- MeTAM or separately, the penten backbone and the MeTAM chelating unit are potentially useful additions to the set of backbones and binding units of multidentate ligands identified as effective for in vivo chelation of the actinides.

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