Flavonoids are nearly ubiquitous in plants and are recognized as the pigments responsible for the colors of leaves, especially in autumn. They are rich in seeds, citrus fruits, olive oil, tea, and red wine. They are low molecular weight compounds composed of a three-ring structure with various substitutions. This basic structure is shared by tocopherols (vitamin E). Flavonoids can be subdivided according to the presence of an oxy group at position 4, a double bond between carbon atoms 2 and 3, or a hydroxyl group in position 3 of the C (middle) ring. These characteristics appear to also be required for best activity, especially antioxidant and antiproliferative, in the systems studied. The particular hydroxylation pattern of the B ring of the flavonoles increases their activities, especially in inhibition of mast cell secretion. Certain plants and spices containing flavonoids have been used for thousands of years in traditional Eastern medicine. In spite of the voluminous literature available, however, Western medicine has not yet used flavonoids therapeutically, even though their safety record is exceptional. Suggestions are made where such possibilities may be worth pursuing.

The Effects of Plant Flavonoids on Mammalian Cells:Implications for Inflammation, Heart Disease, and Cancer

Antioxidant properties of phenolic compounds

This review is directed at understanding how neuronal death occurs in two distinct insults, global ischemia and focal ischemia. These are the two principal rodent models for human disease. Cell dea...

Ischemic Cell Death in Brain Neurons

Byproducts of normal mitochondrial metabolism and homeostasis include the buildup of potentially damaging levels of reactive oxygen species (ROS), Ca2+, etc., which must be normalized. Evidence suggests that brief mitochondrial permeability transition pore (mPTP) openings play an important physiological role maintaining healthy mitochondria homeostasis. Adaptive and maladaptive responses to redox stress may involve mitochondrial channels such as mPTP and inner membrane anion channel (IMAC). Their activation causes intra- and intermitochondrial redox-environment changes leading to ROS release. This regenerative cycle of mitochondrial ROS formation and release was named ROS-induced ROS release (RIRR). Brief, reversible mPTP opening-associated ROS release apparently constitutes an adaptive housekeeping function by the timely release from mitochondria of accumulated potentially toxic levels of ROS (and Ca2+). At higher ROS levels, longer mPTP openings may release a ROS burst leading to destruction of mitochondria, and if propagated from mitochondrion to mitochondrion, of the cell itself. The destructive function of RIRR may serve a physiological role by removal of unwanted cells or damaged mitochondria, or cause the pathological elimination of vital and essential mitochondria and cells. The adaptive release of sufficient ROS into the vicinity of mitochondria may also activate local pools of redox-sensitive enzymes involved in protective signaling pathways that limit ischemic damage to mitochondria and cells in that area. Maladaptive mPTP- or IMAC-related RIRR may also be playing a role in aging. Because the mechanism of mitochondrial RIRR highlights the central role of mitochondria-formed ROS, we discuss all of the known ROS-producing sites (shown in vitro) and their relevance to the mitochondrial ROS production in vivo.

Mitochondrial Reactive Oxygen Species (ROS) and ROS-Induced ROS Release

Spin trapping: ESR parameters of spin adducts.

The production of reactive oxygen species by dietary flavonols

Monoamine oxidase (MAO) as a source of hydrogen peroxide (H2O2) was evaluated during ischemia-reperfusion in vivo in the rat brain. H2O2 production was assessed with and without inhibition of MAO during and after 15 min of ischemia. Metabolism of H2O2 by catalase during ischemia and reperfusion was measured in forebrain homogenates using aminotriazole (ATZ), an irreversible H2O2-dependent inhibitor of catalase. Catecholamine and glutathione concentrations in forebrain were measured with and without MAO inhibitors. During ischemia, forebrain blood flow was reduced to 8% of baseline and H2O2 production decreased as measured at the microperoxisome. During reperfusion, a rapid increase in H2O2 generation occurred within 5 min as measured by a threefold increase in oxidized glutathione (GSSG). The H2O2-dependent rates of ATZ inactivation of catalase between control and ischemia-reperfusion were similar, indicating that H2O2 was more available to glutathione peroxidase than to catalase in this model. MAO inhibitors eliminated the biochemical indications of increased H2O2 production and increased the catecholamine concentrations. Mortality was 67% at 48 h after ischemia-reperfusion, and there was no improvement in survival after inhibition of MAO. We conclude that MAO is an important source of H2O2 generation early in brain reperfusion, but inhibition of the enzyme does not improve survival in this model despite ablating H2O2 production.

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1993.15

Hydrogen peroxide production by monoamine oxidase during ischemia-reperfusion in the rat brain.

The protective role of glutathione in chlorothalonil-induced stoxicity to channel catfish

Objectives: Loxosceles reclusa (brown recluse) spider bites can produce severe skin lesions that may necessitate extensive surgical repair. This study delineated the effects of hyperbaric oxygen (HBO) therapy on these lesions by performing a prospective controlled animal study.

Methods: After approval by the Institutional Animal Care and Use Committee, 41 New Zealand white rabbits received 64 intradermal injections of 73 μL of raw venom extract mixed with physiologic buffered saline (Dulbecco's solution). Control injections were made with buffer. The animals were divided into 5 groups: 1) venom and no HBO; 2) venom and 1 immediate HBO treatment (100% O2); 3) venom and immediate HBO with 10 treatments (100% O2); 4) venom and then delayed (48 hr) HBO therapy with 10 treatments (100% O2); and 5) venom and immediate hyperbaric treatment with normal inspired Po2 for 10 treatments (8.4% O2). Three animals in group 2 also received a control sodium citrate buffer injection. HBO treatments were at 2.5 atm absolute (ATA) for 90 minutes twice daily. Daily measurements were made of the lesion diameter, and skin blood flow using a laser Doppler probe.

Results: There was no significant effect of HBO on blood flow at the wound center or 1–2 cm from the wound center. Standard HBO significantly decreased wound diameter at 10 days (p < 0.0001; ANOVA), whereas hyperbaric treatment with normoxic gas had no effect. Histologic preparations from 2 animals in each group revealed that there were more polymorphonuclear leukocytes in the dermis of all the HBO-treated animals when compared with the venom-alone and sodium-citrate controls.

Conclusion: HBO treatment within 48 hours of a simulated bite from L. reclusa reduces skin necrosis and results in a significantly smaller wound in this model. The mechanism appears unrelated to augmented local blood flow between treatments.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1553-2712.1997.tb03738.x

Brown Recluse Spider Envenomation: A Prospective Trial of Hyperbaric Oxygen Therapy

Since the description of bronchopulmonary dysplasia (BPD) in premature infants, the supplemental oxygen administered has been suspect in the etiology of BPD. This has prompted studies on the effect of hyperoxia on lung growth in neonatal animals. So far, these have not led to a treatment which either prevents or mitigates BPD. Another approach to investigate the effect of hyperoxia on the immature lung is to use lung explants from 12-d gestation mouse fetuses. Exposing explants to different concentrations of oxygen for 48 h, we found that exposures to oxygen both below (10%) and above (35% or greater) normoxia adversely affected branching morphogenesis and growth. The effect was irreversible at exposures of 50% oxygen and greater. To determine the role of reactive oxygen species (ROS) in the effect of hyperoxia, antioxidants and inhibitors of ROS formation were added to the incubating explants, and their influence on reducing the adverse effect of 50% oxygen was assessed. The combination of CuZn superoxide dismutase (SOD) and catalase, manganese SOD, manganese-3-tetrakis(1-methyl-4-pyridyl)porphorin, a low molecular weight SOD mimetic, and to a lesser extent, deferoximine, an antioxidant and inhibitor of hydroxyl radical formation, were successful in reducing the effect of 50% oxygen on morphogenesis. Not successful wereN-nitro-L-arginine methyl ester (an inhibitor of nitric oxide synthase); allopurinol (an inhibitor of xanthine oxidase);N-acetylcysteine and ebselen (a glutathione peroxidase mimetic); Trolox (a synthetic tocopherol); catalase, and CuZnSOD used alone. These results provide evidence that superoxide anion and possibly hydroxyl radical are the ROS most likely responsible for the growth effects of hyperoxia on mouse fetal lung morphogenesis.

/pdf/oxygen-toxicity-to-the-developing-lung-of-the-mouse-role-of-2x6nag6g3l.pdf

Andrew T. Canada

Papers

The production of reactive oxygen species by dietary flavonols

Hydrogen peroxide production by monoamine oxidase during ischemia-reperfusion in the rat brain.

The protective role of glutathione in chlorothalonil-induced stoxicity to channel catfish

Brown Recluse Spider Envenomation: A Prospective Trial of Hyperbaric Oxygen Therapy

Oxygen Toxicity to the Developing Lung of the Mouse: Role of Reactive Oxygen Species