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From Designer Food Formulation to Oxidative Stress Mitigation: Health-Boosting Constituents of Cabbage
Published in Megh R. Goyal, Hafiz Ansar Rasul Suleria, Ramasamy Harikrishnan, The Role of Phytoconstitutents in Health Care, 2020
Faiza Ashfaq, Masood Sadiq Butt, Ahmad Bilal, Kanza Aziz Awan, Hafiz Ansar Rasul Suleria
Initially, the intracellular enzymatic antioxidants become activated as cells’ well-being becomes a threat due to the over-generation of ROS being sensitive to redox state. All the enzymes (SOD, CAT, GPX, GR (glutathione reductase) and GST (glutathione-S-transferase)) work in synergy with nonenzymatic antioxidants (endogenous GSH and exogenous polyphenols or antioxidant vitamins; ascorbate, tocopherols, carotenes, and retinol in diet) to neutralize redox state of cell by converting free radicals to less toxic/reactive compounds or maintaining the free radicals within the tolerable limits. The supportive team of free radical scavengers (CAT, SOD, GST, GPx) and PON1 (paraoxonase 1 – an antioxidant enzyme linked with HDL, calcium-dependent esterase that detoxifies lipid peroxides and widely distributed in numerous tissues) mutually fight against markers of oxidative stress; and products of lipid and protein oxidation include thiobarbituric acid reactive substances, hydroperoxides, and carbonyl proteins.
Biostatistics: Issues in study design, analysis, and reporting
Published in Stephen W. Gutkin, Writing High-Quality Medical Publications, 2018
In the former case, low HDL-C may have been more of a disease marker than a risk factor. Paraoxonase-1, which is genetically encoded and resides within the HDL particle, hydrolyzes inflammatory phospholipids and has other antioxidant functions.17 Enhanced levels (and function) of the HDL particle may be responsible for reducing CVD risk. The cholesterol may have been “along for the ride,” in that high levels of HDL-C are consistent with a favorable “destination” of the cholesterol: through the reverse cholesterol transport pathway to hepatic excretion.
Use of Physiologically Based Pharmacokinetic Modeling to Evaluate Implications of Human Variability
Published in John C. Lipscomb, Edward V. Ohanian, Toxicokinetics and Risk Assessment, 2016
P. Robinan Gentry, Harvey J. Clewell III
It is possible that even though a metabolic enzyme has a polymorphism, the impact on the overall variability for the population may be minimal. This possibility has been suggested in the case of parathion (26). Parathion is metabolized to paraoxon, which can inhibit acetylcholinesterase. Paraoxonase (PON1) is one of the enzymes responsible for the metabolic clearance or detoxification of paraoxon. PON1 is a polymorphic enzyme, with the high-activity PON1 homozygotes accounting for approximately 41% of the U.S. population, the low-activity homozygotes accounting for approximately 15% of the U.S. population, and low/high-activity heterozygotes accounting for approximately 45% of the U.S. population (26–31). Because paraoxon is the active agent, low PON1 activity might be expected to result in increased sensitivity. In vitro data on the two human alleles of paraoxonase (low and high activity) were used to develop distributions for the metabolism parameters to be used in a published PBPK model for parathion (32). As with the warfarin example, Monte Carlo simulations were performed to generate the resulting distribution of predicted blood concentrations of paraoxon across a “normal” or general population (Case 2), considering the variability in other pharmacokinetic parameters.
Pathobiology and evolving therapies of coronary artery vasospasm
Published in Baylor University Medical Center Proceedings, 2021
Monish A. Sheth, Robert J. Widmer, Hari K. Dandapantula
Fujihara et al18 studied polymorphisms in a Japanese population and in three African subethnic groups and found three polymorphisms potentially associated with CAV in Japanese patients: paraoxonase 1 (PON1) Q192R (C/G), endothelial nitric oxide synthase (eNOS) E298D (G/T), and eNOS T-786C. Those with African ethnicities shared a high susceptibility to PON1 Q192R (G) like Japanese patients. The e-NOS mutation was seen in Caucasian populations but mostly in Asian populations. Polymorphism in the paraoxonase gene regulates suppression of oxidative stress. Other notable polymorphisms showed by Murase et al19 studying 2188 Japanese individuals, 500 with CAV and the rest control, found that the NADH/NADPH oxidase p22 phox gene is a susceptibility locus for CAV in men, and the stromelysin-1 and interleukin-6 genes are susceptibility loci in women.
Investigation of the effects of cephalosporin antibiotics on glutathione S-transferase activity in different tissues of rats in vivo conditions in order to drug development research
Published in Drug and Chemical Toxicology, 2020
Fikret Türkan, Zübeyir Huyut, Parham Taslimi, Mehmet Tahir Huyut, İlhami Gülçin
In recent years, inhibition studies of many antibiotics have been performed extensively. These studies were conducted on various enzymes, including paraoxonase (Demir and Beydemir 2015, Türkeş et al.2015). glucose-6-phosphate dehydrogenase (Ozmen et al.2005), 6-phosphogluconate dehydrogenase (Akyüz et al.2004), glutathione reductase (Erat et al.2005), and glutathione S-transferase (Comakli et al.2011). In vivo results from the enzyme activity studies are crucial to recognize the physiological role of the enzyme. Particularly, drug-enzyme or any chemical compound-enzyme interaction studies are important to understand the toxicological mechanisms. In present study, we evaluated cefazolin, cefuroxime, and cefoperazone in vivo inhibition effect on GST enzyme activity. In cefazolin and cefoperazone groups, GST enzyme activities were increased in liver and renal tissues during the first 5 h period, and then began to drop in the next time period. In addition, they were increased in cefuroxime group during firs 3 h period, while began to drop in the next time periods. The situation was showed that the cefazoline and cefaperazon were metabolized after 5th hour and completed their half-life, while cefuroxime were metabolized after 3th hour on GST activity. In addition, after 7 h, it was observed that cefazolin had no adverse effect on GSH enzyme activity in all working tissues, but cefuroxime and cefaperazon caused the decreasing in GST activities compared to control groups after 5th hour period.
The mystery of evacetrapib - why are CETP inhibitors failing?
Published in Expert Review of Cardiovascular Therapy, 2020
Stephen J. Nicholls, Kristen Bubb
Additional approaches to CETP inhibition could take into consideration potential alternative therapeutic uses. In addition to its fundamental role in reverse cholesterol transport, HDL has been demonstrated to possess anti-inflammatory activity [41,42] that may play a role in the response to sepsis. This activity is likely to reflect a number of biological mechanisms, including direct binding of lipopolysaccharide in the setting of systemic endotoxemia [43], in addition to modulating a range of inflammatory pathways either directly or via reduction in generation of lipid peroxidation products [41]. Paraoxonase, a factor carried on HDL, has been demonstrated to possess anti-oxidant activity in vivo in addition to protection against cardiovascular disease [44]. This may also contribute to the anti-inflammatory potential of HDL. Additional observations that Kupfer cells lose their expression of CETP in the setting of gram-negative septicemia, with the resulting HDL playing a potential anti-endotoxin effect [43]. While some have proposed that CETP inhibition may have potential clinical utility in the setting of sepsis, it has also been demonstrated that some of the toxicity observed with torcetrapib involved an increase in mortality attributed to sepsis [11].