scholarly journals Caloric Restriction Mimetics Attenuate the Hallmarks of Aging

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 512-512
Author(s):  
Guido Kroemer
Keyword(s):  
Caloric Restriction ◽  
Cellular Proteins ◽  
Nutrient Depletion ◽  
Acetyl Coenzyme A ◽  
Cellular Effects ◽  
High Throughput Technology ◽  
Screening Assays ◽  
Cancer Immunosurveillance ◽  
Stimulation Of

Abstract Nutrient depletion, which is one of the physiological triggers of autophagy, results in the depletion of intracellular acetyl coenzyme A (AcCoA) coupled to the deacetylation of cellular proteins. We found that there are at least 4 possibilities to mimic these effects, namely (i) the depletion of cytosolic AcCoA by interfering with its biosynthesis, (ii) the stimulation cytosolic AcCoA consumption, (iii) the inhibition of protein acetyltransferases, or (iii) the stimulation of protein deacetylases. Thus, AcCoA depleting agents, AcCoA-consuming agents, acetyltransferase inhibitors or deacetylase activators are highly efficient inducers of autophagy and reduce aging-associated diseases including diabetes, obesity, cardiac failure and failing cancer immunosurveillance. Hence, we classify them as “caloric restriction mimetics” (CRM). We have initiated the systematic search for CRMs based on their cellular effects in vitro. We built screening assays amenable to high-throughput technology for the identification of CRMs. These results will be discussed.

Involvement of nitroxide radicals in cocaine-induced hepatotoxicity

1982 ◽  
Vol 60 (12) ◽  
pp. 1614-1620 ◽  
Author(s):  
Elmer J Rauckman ◽  
Michelle W Kloss ◽  
Gerald M Rosen
Keyword(s):  
Hydrogen Peroxide ◽  
Reduced Glutathione ◽  
Cellular Proteins ◽  
Lipid Hydroperoxides ◽  
Pyridine Nucleotides ◽  
Futile Cycle ◽  
The One ◽  
Cytochrome P 450 ◽  
Stimulation Of

Cocaine administration can produce hepatotoxicity in non-induced mice of at least one strain, DBA/2Ha and hepatotoxicity in induced mice of several strains. Metabolic studies and the administration of metabolites indicate that the minor metabolic pathway, cocaine → norcocaine → N-hydroxynorcocaine → norcocaine nitroxide, is responsible for the observed cocaine-induced hepatotoxicity. In vitro experiments show that cytochrome P-450 can oxidize N-hydroxynorcocaine to norcocaine nitroxide. Norcocaine nitroxide is unreactive towards cellular proteins or glutathione but does react directly with reduced pyridine nucleotides and is rapidly reduced enzymatically by the microsomal flavoproteins, NADPH-cytochrome P-450 reductase and FAD-containing monooxygenase. These reactions constitute a futile cycle in which NADPH is consumed and superoxide and hydrogen peroxide are generated. We postulate that the destruction of hydrogen peroxide by glutathione peroxidase results in the accumulation of excess oxidized glutathione which is actively excreted by the cell, since insufficient NADPH is available for glutathione reductase to maintain the GSH/GSSG ratio at an acceptable level. As reduced glutathione levels diminish, the cell can no longer protect itself against toxic lipid hydroperoxides which accumulate as a result of stimulation of lipid peroxidation (caused by the one electron cycling reaction, N-hydroxynorcocaine to norcocaine nitroxide cycle). Finally, as glutathione is depleted below a certain level, the cell loses the ability to maintain the GSH/GSSG ratio in a range consistent with homeostasis resulting in loss of cellular function. Ultimately, necrosis results. This mechanism is consistent with all the information available concerning cocaine-induced hepatotoxicity.

Early Platelet-Collagen Interactions in Whole Blood and Their Modifications by Aspirin and Dipyridamole Evaluated by a New Method (Basic Wave)

1985 ◽  
Vol 54 (04) ◽  
pp. 799-803 ◽  
Author(s):  
José Luís Pérez-Requejo ◽  
Justo Aznar ◽  
M Teresa Santos ◽  
Juana Vallés
Keyword(s):  
Whole Blood ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
White Blood Cells ◽  
Reversible Aggregation ◽  
Inhibitory Compounds ◽  
Rapid Generation ◽  
Stimulation Of ◽  
Collagen Stimulation

SummaryIt is shown that the supernatant of unstirred whole blood at 37° C, stimulated by 1 μg/ml of collagen for 10 sec, produces a rapid generation of pro and antiaggregatory compounds with a final proaggregatory activity which can be detected for more than 60 min on a platelet rich plasma (PRP) by turbidometric aggregometry. A reversible aggregation wave that we have called BASIC wave (for Blood Aggregation Stimulatory and Inhibitory Compounds) is recorded. The collagen stimulation of unstirred PRP produces a similar but smaller BASIC wave. BASIC’s intensity increases if erythrocytes are added to PRP but decreases if white blood cells are added instead. Aspirin abolishes “ex vivo” the ability of whole blood and PRP to generate BASIC waves and dipyridamole “in vitro” significantly reduces BASIC’s intensity in whole blood in every tested sample, but shows little effect in PRP.

DER EINFLUSS VON RESERPIN AUF DIE ANTITHYREOIDALE WIRKUNG VON KALIUMPERCHLORAT

1962 ◽  
Vol 39 (3) ◽  
pp. 423-430
Author(s):  
H. L. Krüskemper ◽  
F. J. Kessler ◽  
E. Steinkrüger
Keyword(s):  
Thyroid Gland ◽  
Male Rats ◽  
Normal Male ◽  
Tissue Respiration ◽  
List Type ◽  
Morphological Alterations ◽  
Hormone Synthesis ◽  
Stimulation Of

ABSTRACT 1. Reserpine does not inhibit the tissue respiration of liver in normal male rats (in vitro). 2. The decrease of tissue respiration of the liver with simultaneous morphological stimulation of the thyroid gland after long administration of reserpine is due to a minute inhibition of the hormone synthesis in the thyroid gland. 3. The morphological alterations of the thyroid in experimental hypothyroidism due to perchlorate can not be prevented with reserpine.

EFFECT OF ACTINOMYCIN D ON TSH-INDUCED STIMULATION OF THYROIDAL PROTEIN SYNTHESIS IN THE RAT

1974 ◽  
Vol 77 (1) ◽  
pp. 64-70 ◽  
Author(s):  
Gustav Wägar
Keyword(s):  
Protein Synthesis ◽  
Actinomycin D ◽  
The Other ◽  
Leucine Incorporation ◽  
Short Term ◽  
Other Hand ◽  
Thyroid Glands ◽  
Translational Level ◽  
Stimulation Of

ABSTRACT Whether the short-term regulation of thyroidal protein synthesis by TSH occurs at the transcriptional or the translational level was tested by measuring the effect of actinomycin D (act D) on the TSH-induced stimulation of L-14C-leucine incorporation into the thyroidal proteins of rats. TSH was injected 6 h before the rats were killed. The thyroid glands were then removed and incubated in vitro in the presence of L-14C-leucine for 2 h. The pronounced stimulation of leucine incorporation in the TSH-treated animals was depressed as compared with controls but still significant even when the animals had been pre-treated with 100 μg act D 24 and 7 h before sacrifice. On the other hand, act D strongly decreased incorporation of 3H-uridine into RNA. Short-term regulation of thyroidal protein synthesis by TSH appears to be partly but not wholly dependent on neosynthesis of RNA. Hence regulation may partly occur at the translation level of protein synthesis.

Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

2019 ◽  
Vol 22 (8) ◽  
pp. 509-520
Author(s):  
Cauê B. Scarim ◽  
Chung M. Chin
Keyword(s):  
Drug Discovery ◽  
Chagas Disease ◽  
Drug Candidates ◽  
Lead Compounds ◽  
New Drug ◽  
Compound Libraries ◽  
Screening Assays ◽  
Cruzi Infection

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

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