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Antioxidant System Defect Hypothesis


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Oxidative stress mechanisms in tissue injury. Free radical toxicity induced by xenobiotics and the subsequent detoxification by cellular enzymes (termination). Image courtesy of Wikimedia Commons

The 'antioxidant system defect hypothesis' in rosacea patients was mentioned in a report published in Clinical & Experimental Dermatology, Volume 28 Issue 2 Page 188 - March 2003. [1] The report summary stated:

"A possible link between superoxide dismutase activity and malondialdehyde level with the clinical manifestations of rosacea was investigated. We found differences in superoxide dismutase activities between mild rosacea (stages I and II) and severe involvement (stage III) groups, as well as between disease and control groups that were statistically significant (P < 0.05). In the mild involvement group (stages I and II), the superoxide dismutase activity was higher than in the control group (P < 0.05), while the malondialdehyde levels did not differ from the control.

In the severe involvement group (stage III), the superoxide dismutase activity was lower than in the control group (P < 0.05), and this was coupled to a raised level of malondialdehyde (P < 0.05). These findings clearly show that in the mild involvement phase of rosacea patients, superoxide dismutase activity was stimulated to protect the skin against reactive oxygen species so that the malondialdehyde levels were maintained. In contrast, in more severe disease, due to a decrease in the capacity of the antioxidant defence system, the malondialdehyde levels were increased. These findings support the 'antioxidant system defect hypothesis' in rosacea patients." [1] bold added

One indicator of this hypothesis is found in another paper that concluded, "Main finding of our study was that when compared with the control group, serum bilirubin and UA levels were significantly lower in rosacea patients. These levels sustain the hypothesis that antioxidant status and oxidative stress are important in the pathogenesis of rosacea." [11]

Marjorie Lazoff, MD Comments
Marjorie Lazoff, MD commented on the above report back in 2003 with a post at the now defunct Rosacea Knowledge Yahoo Group and here is a reproduction of her post:

"Regardless of its pathogenesis, any physical insult, if severe enough, induces the release of proinflammatory mediators, including ROIs. This is not unique to rosacea, it is a common pathway for injury. In fact, some people hypothesize it as THE common pathway explaining all tissue injury and death, holding the key to perfect health and theoretical immortality. For those not familiar, reactive oxygen species (ROS), including tissue-toxic reactive oxygen intermediates (ROI), are normal byproducts whenever oxygen is metabolized into water -- a process which occurs in every cell of the body. ROIs are potentially damaging to tissues but they are extremely short lived and local enzymes and metabolic processes usually keep ROIs in check. However, increased ROIs are generated in times of high metabolic demands -- illness or other physical stressors, local or systemic inflammation (as in the presence of neutrophils and other immune mediators) -- and also specific environmental forces such as sunlight (to the skin) and smoking and pollution (to the lungs). In these conditions -- and considering genetic, age, and general health status -- protective controls may not be adequate. Local damage from these ROIs occurs, and the damage may even become widespread and deadly. The pathophysiology involving ROIs is called oxidative stress.The damage in oxidative stress includes the lipid-rich cell membranes where, in the presence of ROIs, lipids are abnormally metabolized.

Cell membranes are very important because they filter chemicals going in and out of the cell, and because they house receptors that activate or inhibit cell activities.This study uses common lab measurements to evaluate oxidative stress in the skin of rosaceans. Superoxide dismutase (SOD) is one of many enzymes that destroy ROS, in this case the particular ROS called superoxide. One of the lipid peroxidation metabolites in plasma and cell membrane dysfunction is malondialdehyde (MD). SOD and MD are commonly used to measure oxidative stress in any organ system, or systemically.

I've noticed through the years that some countries, esp in Eastern Europe and Japan, are researching free oxygen radicals and oxidative stress in all diseases, one by one. So taken in context, this is a banal study documenting what was already known -- in ANY inflammatory situation, ROIs are formed. The same group has measured SOD and MD in many other condition -- rosacea is just an example of literally hundreds of diseases where free radical formation can be shown to occur. It gets a little silly -- I recall one Japanese study measured fewer ROSs in children who swam more laps in a pool than other group of children! But most research in this area that I'm familiar with over the past ten years or so is much more serious, and revolves around critical care -- systemic infections, multiple organ failure, heart attacks and brain injuries and other situations when low blood flow, and so decreased oxygen, is occurring. It's truly fascinating stuff but, at present, has unfortunately not yielded many clinical therapies.The article reposted by Matija on rosacea-support about the anti-oxidant properties of topical metronidazole (Metros, Noritate) provides clinical perspective supporting the same view this article does: that rosacea is primarily an inflammatory condition with secondary vascular effects. I don't necessarily agree or disagree but I see it as increasing important theory in understanding rosacea, esp recently over the past five years." [2]

Breaking Down All This for the Faint of Heart
Let's try to break all this down for normal people to understand. First off we have to understand what the 'antioxidant' means when discussing this theory.

An antioxidant "is a molecule that inhibits the oxidation of other molecules." In biology, antioxidants can terminate the chain reaction caused by free radicals resulting from oxidation. 

An oxidant is "is a substance that has the ability to oxidize other substances — in other words to cause them to lose electrons."

In biology, "Oxidation is a chemical reaction that can produce free radicals, leading to chain reactions that may damage cells." 

Free Radicals
Free Radicals, in chemistry are a huge subject, however, in biology, they are "any unstable molecule with one or more unpaired electrons which is formed through normal cell metabolism. Free radicals are also highly reactive and are associated with many disease states. They can lead to the formation of larger groups, also known as reactive oxygen species (ROS). These groups cause DNA damage and other harmful effects." [3]

Oxidative Stress
"Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage." 

Oxidative Stress, Ferritin and Rosacea

Superoxide dismutase
Superoxide dismutase [SOD[ is a class of enzymes that is an important antioxidant defense in nearly all living cells exposed to oxygen. The above report [1] found that SOD activity was higher in mild rosacea group with no difference in the malondialdehyde (MDA) level. MDA is is a marker for oxidative stress. However, in the severe rosacea group SOD was lower and the MDA level was higher. 

Somewhat related to this theory is an article published in a Croatian publication that discusses the "the role of oxidative stress triggered by UV light and iron metabolism in the pathophysiology of rosacea." [4] The article discusses how rosacea patients have significantly higher ferritin, a protein, "which is fundamental in the generation of oxidative stress."

Oxidative Stress, Ferritin and Rosacea

Serum paraoxonase/arylesterase 1 
Serum paraoxonase/arylesterase 1 (PON1) is a glycoprotein that has been found to be decreased in rosacea patients.  "Serum PON1 enzyme activities have decreased significantly in rosacea." [5] This same report [5] states, "Recent evidence suggests that oxidative stress may be an important phenomenon in the pathophysiology of rosacea."

Ozone-oxygen Mixture Treatment
One report that discusses the "possible involvement of pro- and antioxidant imbalance in the pathogenesis of rosacea" proposes "oxidative therapy options for rosacea, treatment with an ozone-oxygen mixture in particular..." [6]

Reactive Oxygen Species [ROS]
"ROS involvement in rosacea pathology has been discussed as explanation for the action of medicines for rosacea treatment." [7]

"Our results suggest that rosacea is an oxidative stress condition, as reflected by the increased ROS activity and decreased AOP, regardless of HP infection." [8]

"A paradox in metabolism is that, while the vast majority of complex life on Earth requires oxygen for its existence, oxygen is a highly reactive molecule that damages living organisms by producing reactive oxygen species." [9]

"In a biological context, ROS are formed as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis. However, during times of environmental stress (e.g., UV or heat exposure), ROS levels can increase dramatically. This may result in significant damage to cell structures. Cumulatively, this is known as oxidative stress." [10]

End Notes

[1] Clin Exp Dermatol. 2003 Mar;28(2):188-92.
The role of free oxygen radicals in the aetiopathogenesis of rosacea.
Oztas MO, Balk M, Ogüs E, Bozkurt M, Ogüs IH, Ozer N.

[2] Marjorie Lazoff, MD at R-K Yahoo group

[3] Free Radicals: Why are they Bad? 7 Tips to Avoid Free Radical Damage, Better Health Organization

[4]Lijec Vjesn. 2011 Jul-Aug;133(7-8):288-91.
The role of oxidative stress and iron in pathophysiology of rosacea
Tisma VS, Poljak-Blazi M.

The above report appears to be a followup to a 2009 paper below 
J Am Acad Dermatol. 2009 Feb;60(2):270-6.
Oxidative stress and ferritin expression in the skin of patients with rosacea

[5] J Eur Acad Dermatol Venereol. 2015 Feb;29(2):367-70. doi: 10.1111/jdv.12556. Epub 2014 May 22.
Decreased serum paraoxonase and arylesterase activities in patients with rosacea.
Takci Z, Bilgili SG, Karadag AS, Kucukoglu ME, Selek S, Aslan M.

[6] Klin Lab Diagn. 2010 Apr;(4):13-6.
Oxidative stress level in patients with rosacea and a rationale for the therapeutic use of an ozone-oxygen mixture.
Bitkina OA, Kopytova TV, Kontorshchikova KN, Bavrina AP.

[7] J Dermatol Sci. 2009 Aug; 55(2): 77–81.
The molecular pathology of rosacea
Kenshi Yamasaki, M.D., Ph.D. and Richard L. Gallo, M.D., Ph.D.

[8] Int J Dermatol. 2004 Jul;43(7):494-7.
Plasma reactive oxygen species activity and antioxidant potential levels in rosacea patients: correlation with seropositivity to Helicobacter pylori.
Baz K, Cimen MY, Kokturk A, Aslan G, Ikizoglu G, Demirseren DD, Kanik A, Atik U.

[9] Antioxidant, Wikipedia

[10] Reactive oxygen species (ROS), Wikipedia

[11] J Cosmet Dermatol. 2020 Mar 31;:
Serum bilirubin and uric acid antioxidant levels in rosacea patients.
Turkmen D

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  • 4 weeks later...
  • Root Admin

Oxygen, ROS and Pathogens

“A paradox in metabolism is that, while the vast majority of complex life on Earth requires oxygen for its existence, oxygen is a highly reactive molecule that damages living organisms by producing reactive oxygen species." [1]

"However, reactive oxygen species can be beneficial, as they are used by the immune system as a way to attack and kill pathogens." [2]

The human body composition can be "analyzed in various ways," either by chemical elements present, or by molecular type. "Almost 99% of the mass of the human body is made up of six elements: oxygen (65%), carbon (18.5%), hydrogen (9.5%), nitrogen (3.2%), calcium (1.5%), and phosphorus (1%)." [3] Oxygen makes up 65% of the chemical element in the human body, while water makes up 65% of the molecular mass. Another method to analyze the human body is by cell type. "Traditionally, non human microorganisms in the human body have been estimated to be way more than human organisims, depending on what you designate is actually 'human',  but more recent estimates put this number at a 50/50 ratio, so, this subject is debated among biologists" [4]

So oxygen is important in human metabolism and comprises the majority of the composition of the body. However, sometimes oxygen can cause negative reaction in disease as this thread is pointing out with ROS and its connection to rosacea. If you have a pathogen issue causing rosacea, I.e., demodexvirus, or bacteria, ROS activates the immune system response, which may cascade an inflammatory reaction. 

End Notes

[1] Antioxidant, Wikipedia

[2] Oxidative stress, Wikipedia

[3] Composition of the Human Body, Wikipedia

[4] Human Microbiome, Brady Barrows



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"Skin, the largest organ in the human body, is exposed to air pollutants, including diesel exhaust fumes, ultraviolet rays, food, xenobiotics, drugs, and cosmetics, which promote the production of ROS. ROS exacerbate skin aging and inflammation, but also function as regulators of homeostasis in the human body, including epidermal keratinocyte proliferation. Although ROS have been implicated in various skin diseases, the underlying mechanisms have not yet been elucidated." [1]

"The regulation of free radical and ROS has been implicated in the development of various skin diseases; however, the underlying mechanisms have not yet been elucidated in detail, and proper usage of antioxidant drugs is still unknown now. In addition, there lacks studies concerning physiological roles of free radicals and ROS in skin homeostasis, and the information about duration of the generation, action and ratio of free radicals and ROS is still unclear in skin diseases.'

[1] What Are Reactive Oxygen Species, Free Radicals, and Oxidative Stress in Skin Diseases?

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