In vivo studies on the target tissue metabolism, covalent binding, glutathione depletion, and toxicity of 4-ipomeanol in birds, species deficient in pulmonary enzymes for metabolic activation

1982 ◽  
Vol 65 (1) ◽  
pp. 38-52 ◽  
Author(s):  
Alan R. Buckpitt ◽  
Charles N. Statham ◽  
Michael R. Boyd
Keyword(s):  
Covalent Binding ◽  
Metabolic Activation ◽  
Glutathione Depletion ◽  
In Vivo Studies ◽  
Target Tissue ◽  
Tissue Metabolism

scholarly journals Resistin Is Increased in Periodontal Cells and Tissues: In Vitro and In Vivo Studies

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Andressa V. B. Nogueira ◽  
Marjan Nokhbehsaim ◽  
Sema Tekin ◽  
Rafael S. de Molon ◽  
Luis C. Spolidorio ◽  
...  
Keyword(s):  
Bone Loss ◽  
Inflammatory Diseases ◽  
Inflammatory Cells ◽  
Male Rats ◽  
In Vivo Studies ◽  
Hard Tissue ◽  
Tissue Metabolism ◽  
Inflammatory Stimuli

Resistin, a proinflammatory adipokine, is elevated in many inflammatory diseases. However, little is known about its performance in periodontitis. The present study is aimed at evaluating resistin expression and synthesis in periodontal cells and tissues under inflammatory/microbial stress in addition to its effects on the periodontium. In vivo, 24 male rats were randomly divided into two groups: control and ligature-induced periodontal disease. After 6 and 12 days, animals were sacrificed to analyze gene expression of adipokines, bone loss, inflammation, and resistin synthesis. In vitro, human periodontal ligament (PDL) fibroblasts were used to evaluate the expression of resistin after inflammatory stimuli. In addition, PDL fibroblasts were exposed to resistin to evaluate its role on soft and hard tissue metabolism markers. The periodontitis group demonstrated significant bone loss, an increase in the number of inflammatory cells and vascular structures, an increase in resistin expression and synthesis, and a decrease in the expression of adiponectin, leptin, and its functional receptor. PDL fibroblasts showed a significant increase in resistin expression and synthesis in response to the inflammatory stimulus by IL-1β. Resistin induced an increase in cytokine expression and a decrease in the regulation of some hard tissue and matrix formation genes in PDL fibroblasts. These data indicate that resistin is produced by periodontal cells and tissues, and this effect is enhanced by inflammatory stimuli. Moreover, resistin seems to interfere with soft and hard tissue metabolism during periodontitis by reducing markers related to matrix formation and bone tissue.

scholarly journals Pilot in vivo studies on transcutaneous boiling histotripsy in porcine liver and kidney

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Tatiana D. Khokhlova ◽  
George R. Schade ◽  
Yak-Nam Wang ◽  
Sergey V. Buravkov ◽  
Valeriy P. Chernikov ◽  
...  
Keyword(s):  
Peak Power ◽  
Ex Vivo ◽  
Respiratory Gating ◽  
Subcutaneous Fat ◽  
High Intensity Focused Ultrasound ◽  
In Vivo Studies ◽  
Swine Model ◽  
Target Tissue ◽  
Porcine Liver

AbstractBoiling histotripsy (BH) is a High Intensity Focused Ultrasound (HIFU) method for precise mechanical disintegration of target tissue using millisecond-long pulses containing shocks. BH treatments with real-time ultrasound (US) guidance allowed by BH-generated bubbles were previously demonstrated ex vivo and in vivo in exposed porcine liver and small animals. Here, the feasibility of US-guided transabdominal and partially transcostal BH ablation of kidney and liver in an acute in vivo swine model was evaluated for 6 animals. BH parameters were: 1.5 MHz frequency, 5–30 pulses of 1–10 ms duration per focus, 1% duty cycle, peak acoustic powers 0.9–3.8 kW, sonication foci spaced 1–1.5 mm apart in a rectangular grid with 5–15 mm linear dimensions. In kidneys, well-demarcated volumetric BH lesions were generated without respiratory gating and renal medulla and collecting system were more resistant to BH than cortex. The treatment was accelerated 10-fold by using shorter BH pulses of larger peak power without affecting the quality of tissue fractionation. In liver, respiratory motion and aberrations from subcutaneous fat affected the treatment but increasing the peak power provided successful lesion generation. These data indicate BH is a promising technology for transabdominal and transcostal mechanical ablation of tumors in kidney and liver.

scholarly journals Preparation and Preliminary Evaluation of Novel β-Cyclodextrin/IUDR Prodrug Formulations

2008 ◽  
Vol 11 (2) ◽  
pp. 32 ◽  
Author(s):  
Leonard I. Wiebe ◽  
Xiao-Hong Yang ◽  
Shradha Singh ◽  
Jim Diakur
Keyword(s):  
Inclusion Complexes ◽  
In Vivo Studies ◽  
Preliminary Evaluation ◽  
Target Tissue ◽  
Molar Ratios ◽  
Nmr Spectrometry ◽  
Complex Approach ◽  
The Stability

PURPOSE. Iododeoxyuridine (IUdR) has a very short in vivo half-life and consequently achieves low target-tissue concentrations with concomitant lower efficacy than would be predicted from in vitro studies. This work reports the preparation of IUdR:?-cyclodextrin (?-CyD) inclusion complexes designed to reduce in vivo inactivation of IUdR. METHODS. IUdR was derivatized with either 1-adamantanecarbonyl chloride or 4-(1-adamantyl-carbamoyl)butanoic acid, to prepare 5’-O-(1-adamantoyl)-5-iodo-2’-deoxyuridine 1 and 5’-O-(4-(1-adamantylcarbamoyl)butoyl)-5-iodo-2’-deoxy-uridine 4, respectively. ?-CyD complexes 5 and 6 were formed by vigorous stirring of 1:1 solutions of ?-CyD and 1 or 4, respectively, in D2O under argon. Complexation was inferred from DSC, powder x-ray diffractometry and NMR spectrometry. The dissociation of 5 in water and under cholesterol challenge, and the effect of complexation on the stability of 1 was determined by incubation in plasma. RESULTS. IUdR coupling with adamantanecarbonyl chloride proceeded smoothly to afford 1 (69 %) and the di-substituted derivative, 3’,5’-di-O-(1-adamantoyl)-5-iodo-2’-deoxyuridine 2 (8 %); 4 was obtained in 42 % yield. The formation of 1:1 complexes 5 and 6 was inferred from NMR chemical shift data. In serum, 1 was 90 % hydrolyzed to IUdR in 30 min, compared to 10 % hydrolysis of 1 to IUdR when from complex 5. CONCLUSIONS. Inclusion complexes were formed between ?-CyD and adamantamine-IUdR conjugates at 1:1 molar ratios. The complex 5 was resistant to dissociation by cholesterol challenge, and 5 was more slowly converted to IUdR than non-complexed 1. In vivo studies are required to further exploit the ?-CyD inclusion complex approach for improved delivery of nucleoside derivatives.

scholarly journals Metabolic activation of acetylenic substituents to derivatives in the rat causing the loss of hepatic cytochrome P-450 and haem

1978 ◽  
Vol 174 (3) ◽  
pp. 853-861 ◽  
Author(s):  
Ian N. H. White
Keyword(s):  
Covalent Binding ◽  
Metabolic Activation ◽  
Microsomal Protein ◽  
Significant Loss ◽  
Microsomal Cytochrome ◽  
Rf Values ◽  
Green Pigments ◽  
Cytochrome P 450

1. A number of acetylenic-substituted steroidal and non-steroidal compounds, including 2,2-dipropargylacetamide, pregna-2,4-dien-20-yno[2,3-d]isoxazol-17-ol (Danazol) and acetylene gas, when administered to rats in vivo brought about a decrease in the concentrations of hepatic microsomal cytochrome P-450 and haem. Abnormal haem-breakdown products, ‘green pigments’, and porphyrins accumulated in the livers of these animals. 2. For loss of microsomal cytochrome P-450 to occur in vitro, metabolic activation of the acetylenic substituent was necessary. The enzyme system responsible required NADPH and air, and was induced by pretreatment of rats with phenobarbitone; these are characteristics typical of the microsomal mixed-function oxidases. 3. When rats were dosed with 17α-ethynyl-17β-hydroxyandrost-4-en-3-one (ethynyltestosterone, 1mmol/kg) the pattern of green pigments extracted from the liver 4h after dosing and separated by t.l.c. was quite different from that in rats given 17β-hydroxy-17α-vinylandrost-4-en-3-one (vinyltestosterone), suggesting that reduction of the unsaturated triple bond to a double bond is not normally part of the metabolic activation pathway of the acetylenic substituent. 4. The green pigments extracted from the livers of rats 4h after the administration of the acetylenic-substituted compounds (1mmol/kg) when separated by silica-gel t.l.c. had variable RF values. The number and distribution of green pigments was characteristic for each compound examined. There was little correlation between the total loss of hepatic microsomal haem and the apparent intensity of the green pigments seen on the thin-layer chromatograms. 5. After incubation of [14C]acetylene in vitro with microsomal preparations from phenobarbitone-pretreated rats and a NADPH-generating system, no significant covalent binding to microsomal protein was detected over a 30min incubation period, although under similar conditions there was a significant loss of cytochrome P-450.

In vitro and in vivo studies of the metabolic activation of chelidonine

2019 ◽  
Vol 308 ◽  
pp. 155-163
Author(s):  
Yuyang Liu ◽  
Ying Peng ◽  
Zhengyu Zhang ◽  
Xiucai Guo ◽  
Mingshan Ji ◽  
...  
Keyword(s):  
Metabolic Activation ◽  
In Vivo Studies

In Vitro and in Vivo Studies of the Metabolic Activation of 8-Epidiosbulbin E Acetate

2015 ◽  
Vol 28 (9) ◽  
pp. 1737-1746 ◽  
Author(s):  
Dongju Lin ◽  
Xiucai Guo ◽  
Huiyuan Gao ◽  
Li Cheng ◽  
Maosheng Cheng ◽  
...  
Keyword(s):  
Metabolic Activation ◽  
In Vivo Studies

scholarly journals Establishment of Novel Genotoxicity Assay System Using Murine Normal Epithelial Tissue-Derived Organoids

2021 ◽  
Vol 12 ◽  
Author(s):  
Masami Komiya ◽  
Rikako Ishigamori ◽  
Mie Naruse ◽  
Masako Ochiai ◽  
Noriyuki Miyoshi ◽  
...  
Keyword(s):  
Safety Assessment ◽  
General Procedure ◽  
Metabolic Activation ◽  
Chemical Carcinogenesis ◽  
Dna Adduct ◽  
Organ Specificity ◽  
Epithelial Tissue ◽  
Target Tissue ◽  
Middle Term

Short-/middle-term and simple prediction studies for carcinogenesis are needed for the safety assessment of chemical substances. To establish a novel genotoxicity assay with an in vivo mimicking system, we prepared murine colonic/pulmonary organoids from gpt delta mice according to the general procedure using collagenase/dispase and cultured them in a 3D environment. When the organoids were exposed to foodborne carcinogens—2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) and acrylamide (AA)—in the presence of metabolic activation systems, mutation frequencies (MFs) occurring in the gpt gene dose-dependently increased. Moreover, the mutation spectrum analysis indicated predominant G:C to T:A transversion with PhIP, and A:T to C:G and A:T to T:A transversion with AA. These data correspond to those of a previous study describing in vivo mutagenicity in gpt delta mice. However, organoids derived from the liver, a non-target tissue of PhIP-carcinogenesis, also demonstrated genotoxicity with a potency comparable to colonic organoids. Organoids and PhIP were directly incubated in the presence of metabolic activation systems; therefore, there was a lack of organ specificity, as observed in vivo. Additionally, PhIP-DNA adduct levels were comparable in hepatic and colonic organoids after PhIP exposure. Taken together, the organoids prepared in the present study may be helpful to predict chemical carcinogenesis.

scholarly journals Heterometallic Ru–Pt metallacycle for two-photon photodynamic therapy

2018 ◽  
Vol 115 (22) ◽  
pp. 5664-5669 ◽  
Author(s):  
Zhixuan Zhou ◽  
Jiangping Liu ◽  
Thomas W. Rees ◽  
Heng Wang ◽  
Xiaopeng Li ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Singlet Oxygen ◽  
Near Infrared ◽  
Photon Absorption ◽  
In Vivo Studies ◽  
Target Tissue ◽  
Noninvasive Treatment ◽  
Two Photon Absorption ◽  
Two Photon

As an effective and noninvasive treatment of various diseases, photodynamic therapy (PTD) relies on the combination of light, a photosensitizer, and oxygen to generate cytotoxic reactive oxygen species that can damage malignant tissue. Much attention has been paid to covalent modifications of the photosensitizers to improve their photophysical properties and to optimize the pathway of the photosensitizers interacting with cells within the target tissue. Herein we report the design and synthesis of a supramolecular heterometallic Ru–Pt metallacycle via coordination-driven self-assembly. While inheriting the excellent photostability and two-photon absorption characteristics of the Ru(II) polypyridyl precursor, the metallacycle also exhibits red-shifted luminescence to the near-infrared region, a larger two-photon absorption cross-section, and higher singlet oxygen generation efficiency, making it an excellent candidate as a photosensitizer for PTD. Cellular studies reveal that the metallacycle selectively accumulates in mitochondria and nuclei upon internalization. As a result, singlet oxygen generated by photoexcitation of the metallacycle can efficiently trigger cell death via the simultaneous damage to mitochondrial function and intranuclear DNA. In vivo studies on tumor-bearing mice show that the metallacycle can efficiently inhibit tumor growth under a low light dose with minimal side effects. The supramolecular approach presented in this work provides a paradigm for the development of PDT agents with high efficacy.

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