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Advancements in Free-Radical Pathologies and an Important Treatment Solution with a Free-Radical Inhibitor

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Advancements in Free-Radical Pathologies and an Important Treatment Solution with a Free-Radical Inhibitor

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Unsaturated carbon-carbon double bonds particularly at exposed end groups of nonsolid fluids are susceptible to free-radical covalent bonding on one carbon atom creating a new free radical on the opposite carbon atom. Subsequent reactive secondary sequence free-radical polymerization can then continue across extensive carbon-carbon double bonds to form progressively larger molecules with ever-increasing viscosity and eventually produce solids. In a fluid solution when carbon-carbon double bonds are replaced by carbon-carbon single bonds to decrease fluidity, increasing molecular organization can interfere with molecular oxygen (O2) diffusion. During normal eukaryote cellular energy synthesis O2 is required by mitochondria to combine with electrons from the electron transport chain and hydrogen cations from the proton gradient to form water. When O2 is absent during periods of irregular hypoxia in mitochondrial energy synthesis, the generation of excess electrons can develop free radicals or excess protons can produce acid. Free radicals formed by limited O2 can damage lipids and proteins and greatly increase molecular sizes in growing vicious cycles to reduce oxygen availability even more for mitochondria during energy synthesis. Further, at adequate free-radical concentrations a reactive crosslinking unsaturated aldehyde lipid breakdown product can significantly support free-radical polymerization of lipid oils into rubbery gel-like solids and eventually even produce a crystalline lipid peroxidation with the double bond of O2. Most importantly, free-radical inhibitor hydroquinone intended for medical treatments in much pathology such as cancer, atherosclerosis, diabetes, infection/inflammation and also ageing has proven extremely effective in sequestering free radicals to prevent chain-growth reactive secondary sequence polymerization.
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Advancements in Free-Radical Pathologies and an Important
Treatment Solution with a Free-Radical Inhibitor
RC Petersen1,*, MS Reddy2, and P-R Liu3
1Departments of Biomaterials and Restorative Sciences, University of Alabama at Birmingham,
USA
2Office of the Dean, School of Dentistry, University of Alabama at Birmingham, USA
3Department of Restorative Sciences, University of Alabama at Birmingham, USA
Abstract
Unsaturated carbon-carbon double bonds particularly at exposed end groups of nonsolid fluids are
susceptible to free-radical covalent bonding on one carbon atom creating a new free radical on the
opposite carbon atom. Subsequent reactive secondary sequence free-radical polymerization can
then continue across extensive carbon-carbon double bonds to form progressively larger molecules
with ever-increasing viscosity and eventually produce solids. In a fluid solution when carbon-
carbon double bonds are replaced by carbon-carbon single bonds to decrease fluidity, increasing
molecular organization can interfere with molecular oxygen (O2) diffusion. During normal
eukaryote cellular energy synthesis O2 is required by mitochondria to combine with electrons from
the electron transport chain and hydrogen cations from the proton gradient to form water. When
O2 is absent during periods of irregular hypoxia in mitochondrial energy synthesis, the generation
of excess electrons can develop free radicals or excess protons can produce acid. Free radicals
formed by limited O2 can damage lipids and proteins and greatly increase molecular sizes in
growing vicious cycles to reduce oxygen availability even more for mitochondria during energy
synthesis. Further, at adequate free-radical concentrations a reactive crosslinking unsaturated
aldehyde lipid breakdown product can significantly support free-radical polymerization of lipid
oils into rubbery gel-like solids and eventually even produce a crystalline lipid peroxidation with
the double bond of O2. Most importantly, free-radical inhibitor hydroquinone intended for medical
treatments in much pathology such as cancer, atherosclerosis, diabetes, infection/inflammation and
also ageing has proven extremely effective in sequestering free radicals to prevent chain-growth
reactive secondary sequence polymerization.
Keywords
Free radical; Molecular oxygen; Reactive oxygen species; Reactive secondary sequence;
Polymerization; Lipid peroxidation; Membrane fluidity; Free-radical inhibitor
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
*Correspondence: Petersen RC, Department of Biomaterials and Restorative Sciences, University of Alabama at Birmingham, SDB
539 1919 7th Avenue South, USA., Tel: 949-429-8537, richbme@uab.edu.
HHS Public Access
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Introduction
Free-radical polymerization is one of the most important chemistries in the world today key
to many diverse applications including use in the development for various types of aerotech
structures, aircraft, marine manufacturing, commercial/military cars and trucks, ballistic
material, medical bone cements, many dental restoratives, water resistant surface protection
and repairs. A breakthrough in free-radical chemistry is distinguished by reactive secondary
sequence covalent bonding through multiple carbon-carbon double bonds especially during
intermittent hypoxia that provides significant understanding to most known medical states
[1–3]. Free radicals are extremely unstable molecules with an unpaired electron in an outer
valence orbital that needs an extra electron to restore stability [4–6]. Unsaturated carbon-
carbon double bonds particularly at exposed end groups are especially susceptible to a free-
radical forming a covalent single bond on one carbon atom to create a new free radical on
the opposite carbon atom [1,2]. Reactive secondary sequence free-radical bonding can then
continue a polymerization chain-growth reaction across numerous carbon-carbon double
bonds to form larger molecules or ultimately macromolecular polymers [1,2].
Cellular mitochondrial organelles produce over 90% of the adenosine triphosphate for the
cell during aerobic energy synthesis [7,8]. As a result, mitochondria consume approximately
85% of all cellular O2 [9]. However, during hypoxic aerobic conditions mitochondria also
produce electrons that are the chief source for free radicals as reactive oxygen species (ROS)
like superoxide anion (O2•−) by the one electron reduction of O2 [9–16]. ROS comprise
O2•−, hydrogen peroxide (H2O2) and the hydroxyl radical (HO) [1,2,9,17]. The free radical
O2•− and HO are unstable molecules with an unpaired electron [1,2]. Alternatively, H2O2 is
a moderately stable molecule but can produce HO when exposed to transition metal cations
for example divalent ferrous iron or Fe+2 [1] common to the heme molecule [18] and found
in connective tissue [19,20]. High levels of ROS generated through mitochondria can cause
damage to lipids, proteins and DNA [17,21–30]. Further, ROS can augment pathology
[1,3,15,17,22,25,27,30] and even increase ageing [9,19,20,24,31]. On the other hand, ROS
can provide a level of biology for physiologic protection at low concentrations
[17,21,22,30,32–36].
Mitochondria require O2 during energy metabolism so that electrons generated through the
electron transport chain and protons that develop around the proton gradient can combine
with help from proteins that are enzymes to form water (Figure 1). In the process of
mitochondrial aerobic metabolism NADH is oxidized to NAD+ releasing 2 electrons and a
proton. Without O2 during mitochondrial energy synthesis excess electrons can form free
radicals and protons can produce acid [1,2]. When combined with acid free radicals can
break down large lipids such as polyunsaturated fatty acids (PUFAs) and with possible help
from enzymes produce smaller reactive unsaturated aldehydes that greatly increase free-
radical crosslinking reactive secondary sequence polymer chemistry [1,2]. Lipids are
classified by two types as simple fats and waxes with hydrolyzable ester linkages between
fatty acids and glycerol or as complex ring structures like cholesterol and other steroids
without ester linkages [37]. Simple lipids are further categorized by the fatty acid chains as
fats or oils in relation to the amount of bond saturation or also carbon-carbon double bonds
respectively [37,38]. When the number of carbon-carbon double bonds is lowered saturation
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is increased with greater amounts of hydrogen-carbon bonds for higher melting points and
unsaturated low viscosity oils can become solid-like saturated fats [37]. Free radicals
produced as a result of O2 structural barriers and decreased O2 diffusion to mitochondria are
then possibly accessible for chain growth polymerization crosslinking with the reactive
unsaturated aldehydes by covalent bonding across PUFA double bonds to increase molecular
structure to a great extent [1,2]. Subsequent PUFA double-bond reactive secondary sequence
crosslinking can then generate an increasing run-away spiral of molecular barrier structures
to O2 diffusion and lower O2 availability for mitochondria during energy synthesis resulting
in continuing ever-greater production of free radicals [1,2].
Free radicals can interact for increased structural organization by molecular crosslinking to
reduce O2 transport at the molecular, cellular, tissue and vascular levels that may generate
pathology in cancer, atherosclerosis, diabetes, trauma, inflammation and infection as basic
examples. Free-radical ROS at the normal low levels are considered to be part of cell
physiology for example with antimicrobial oxidative bursts to destroy microbes, control
autophagy to reuse intracellular organelles or molecules by a type of nutrition biosynthesis,
provide a form of cell signaling as a way of adapting to stress and following trauma support
healing in association with molecular growth factors [17,21,22,30,32–36]. But, at higher
free-radical levels molecules such as lipids, proteins and DNA can be damaged [17,21–30].
When free-radical crosslinking occurs between unsaturated lipids especially in the presence
of low molecular-weight reactive unsaturated lipid aldehyde breakdown products the low oil
viscosity can increase and eventually produce rubbery solids and even crosslink between the
double bonds of O2 concentrated near a nonpolar interface to generate crystalline lipid
peroxidation products [1] (Figures 2 and 3). With sufficient concentration levels of free-
radicals and reactive unsaturated aldehydes the unsaturated lipid polymerization process is
thermodynamically favorable even at just room temperature [1]. During covalent free-radical
reactive secondary sequence crosslinking lipid oils increase viscosity [1,2] and cell
membranes can draw together to become less rounded with decreased fluidity so that
molecular oxygen diffusion through the membrane is reduced [2]. Also, free radicals can
stiffen the extracellular matrix as in many cancers [39–45]. Further, by free-radical reactive
secondary sequence polymerization the lipid core of plaque lesions in atherosclerosis can
develop hardness with size enlargement [1,36] as part of a complex process that may restrict
blood flow [36]. Multiple initiating events that start the cascading reductions in transport of
O2 could include many combined factors from toxicity of environmental chemical
interactions or improper nutrition, ionizing radiation, tissue trauma with irregular healing
and scarring, various infections coordinated with damaging inflammation, vascular
obstructions, increased extracellular matrix stiffness, or reduced cell membrane fluidity to
name a few associated events or initiating sources.
Cell Membranes
Free radicals can result in reducing membrane fluidity to increase membrane rigidity
[2,9,46–50]. Most importantly, free radicals target PUFAs that lower in content as a sign
crosslinking occurs with loss of carbon-carbon double bonds [46–50]. When the fatty acid
saturated/unsaturated ratio increases membrane fluidity can also decrease due to increased
molecular packing by saturated single bond rotation entanglements compared to
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unsaturation with carbon-carbon double bonds that reduce bond entanglements [2,51,52].
Further, membrane fluidity can decrease by increasing the fatty acid chain lengths [51].
Conversely, membrane fluidity can increase during free-radical electrophilic attack with
hydrolysis on PUFA carbon-carbon double bonds [2,53,54] by oxidative cleavage forming
smaller molecules as relatively unreactive aldehydes that can travel easier into less
significant spaces [1]. Increased fluidity occurs as a result of smaller molecules increasing
diffusion exponentially whereas longer molecules decrease movement by single bond
rotation entanglements [55]. The Fluid Mosaic Membrane Model offers the best accepted
insight into limitations on lateral diffusion of lipids and proteins within the membrane
[56,57]. The present Fluid Mosaic Membrane Model illustrates how lateral protein mobility
is dependent on membrane fluidity along with protein size or protein aggregation [58]. As a
result, within the membrane lateral molecular movement allows lipids and proteins to search
for molecules of similar covalent polarities by weak attractive forces [2]. Saturated lipids
that form as more rigid-like macromolecules from unsaturated lipid oils to reduce more fluid
membrane regions appear to be influenced through free-radical ROS crosslinking into lipid
rafts by demonstrating increased saturated amounts with increasing H2O2 [50]. Structural
rigidity organization of the plasma cell membrane increases for lower fluidity as a
consequence of ageing [9]. Further, oxidative damage decreases fluidity of the inner
mitochondrial membrane [9]. Plasma cell membrane unsaturated fatty acids and especially
PUFAs are especially at risk to ROS electrophilic attack [49,50] because of susceptible
carbon-carbon double π bonds that in turn create lipid products with saturated single σ
bonds [1,2]. Regarding other ROS influences to increase membrane rigidity and reduce
molecular lateral diffusion, proteins are found to agglomerate or crosslink when exposed to
ROS for example by dityrosine crosslinks with metal catalyzed reactions [59–61], through
cysteine disulfide crosslinks [62,63] or from the reactive unsaturated aldehyde acrolein that
crosslinks amino acids with serine, histidine, arginine, theronine and lysine being most
susceptible [64].
Erythrocytes with high concentrations of PUFAs exposed to ROS experience reduced
fluidity that indicates free radicals are involved by crosslinking [48,49]. Also, erythrocyte
membranes deform when exposed to ROS developing a pointed extension [49] similar to
pointed membrane extensions that are traits of free-radical crosslinked cancer cells [3].
Consequently, PUFA free-radical crosslinked stiffer membranes during irregular hypoxic
conditions with mitochondrial energy synthesis could explain loss of membrane fluidity and
resultant pathology [2]. In addition, longevity is thought to increase with lower fatty acid
unsaturation levels due to less exposure of carbon-carbon π bonds vulnerable to ROS attack
[65].
Nonpolar O2 diffuses through the nonpolar cell membrane phospholipids by similar polarity
attractions to ultimately combine with excess electrons and protons during mitochondrial
energy synthesis [1,2]. Also, lateral motion of lipids and proteins in the membrane requires
sufficient fluidity [58]. But, with irregular hypoxic conditions electron radicals can generate
from the mitochondrial electron transport chain and hydrogen cations can increase from the
proton gradient [1,2]. As a result of hypoxic environments, membrane fluidity can be
decreased by free-radical crosslinking with PUFAs [9,46–50]. ROS also influence lowering
membrane fluidity and reduced molecular lateral diffusion by agglomerating or crosslinking
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proteins [59–64]. Resultant reductions in membrane fluidity consequently interfere with
diffusion of O2 [66–68]. Less O2 available for normal mitochondrial energy synthesis in turn
produces more free radicals [1–3]. Consequently, an escalation of free-radical concentrations
over time can increase membrane PUFA crosslinking to reduce membrane fluidity with
increased macromolecular barriers to decrease O2 diffusion even more [2]. As free-radical
concentrations rise molecular degenerative insults accumulate on lipids, proteins and DNA
[17,21–30]. Subsequent build up of free-radical damage is considered an important
component for many medical conditions [1,3,17,22,25,27,30] and even ageing
[9,19,20,24,31].
Cancer
As presented previously, elevated pathologic ROS levels and oxidative damage can decrease
membrane fluidity [2,9,46–50]. Hypoxia in cancer cells produces high concentrations of free
radicals [3,69–77], expected by irregular O2 availability to mitochondria during energy
synthesis to generate the superoxide anion O2•− [9,15,16,31,54,78–80]. Cancer cell
membranes reflect oxidative stress by ROS with uneven distorted borders, membrane
ruffling and irregularly shaped nuclei compared to smoother more even rounder membranes
of normal cells with smooth nuclei [3]. A notable expression of free-radical covalent bond
polymerization is the linear or volumetric shrinkage from the original fluid-like material
toward a harder and smaller more solid mass [1–3,81–84]. Also, free-radical polymerization
shrinkage creates a distortion or warpage at some level because of uneven covalent bonding
[1–3,81,83,84]. Uneven nonuniform polymerization shrinkage with warpage is enhanced
with film coatings having uneven depth without smooth regular support underneath [84].
Cytoskeletal actin fibers provide strength inside the plasma cell membrane [85]. Unsaturated
lipid oils of the plasma cell membrane would then crosslink over supporting actin fibers set
irregularly beneath to increase polymerization shrinkage warpage [3]. Unsaturated lipids
pulled together by free-radical covalent crosslinking at rounder more even membrane
borders would need invagination to wrinkle inward particularly when coupled with irregular
actin fiber support underneath to explain the distorted appearance that occurs during the
transformation to cancer cells [3]. Related to irregular uneven cancer cell membranes,
vitamin A and β,β-carotene nutrient capsules both with numerous multiple carbon-carbon
double bonds in unsaturated oil suspensions produced extensive wrinkling and warpage
during free-radical polymerization into solid rubbery gels [1] (Figure 4). Similar to carbon-
carbon double bond polymerization shrinkage with warpage, cell cultures demonstrate
comparisons between normal smoother membranes in contrast to cancer cells with more
distorted uneven membranes that include spike-type extensions to create deeper invaginated
borders (Figure 5).
Cancer transformation entails cell movement through an epithelial-mesenchymal transition
(EMT) with alterations in cell shape and invasion of neighboring tissue [85,86]. Cancer cells
have shown motility responses to ROS with H2O2 that can degrade into HO and produce
projections at the cell membrane borders [87,88]. Chemotaxis has been sustained by ROS as
H2O2 to direct chemotaxis by controlling chemoattractants that connect to the cell
membrane with actin polymerization for cell movement toward H2O2 and other ROS [89–
91]. Cell membrane projections can generate adhesive attachments to the extracellular
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matrix that are able to contract as molecular bonds develop to advance the cell forward
[87,92,93]. Mitochondrial electrons appear capable of delocalizing during oxidative stress
through microtubules and actin fibers out to the plasma cell membrane [3]. Free-radical
covalent bond crosslinking and weak secondary bonding supply a method for contraction
that can bring large macromolecular structures closer together [1,82–84] and provide
forward cell movement [2,3]. Polymerization of actin can extend fibers outward from the
plasma cell membrane creating projections that contain focal adhesions to the extracellular
matrix and advance the cell forward as adhesive bonds form to contract [87,92,93]. Cancer
plasma cell membranes demonstrate the irregular membrane borders with ruffling and wide
spike-like projections lengthening away from the cell (Figure 6).
Despite spike-like projections extending from the cancer plasma cell membrane that could
interfere with mobility, invasive cancer cells have smaller membrane surface areas with
lower modulus to provide flexibility and better facilitate squeezing through small spaces
such as openings in the blood vessel endothelium [94]. Nevertheless, spike-like projections
are a strong characteristic on the leading edge of cancer cells during metastatic movement
[95]. Actin fibers align along the axis of the membrane extensions for highest modulus to
resist sideways deflections in the forward direction [95]. As the stiff membrane extensions
squeeze through small spaces leverage can be applied to force such narrow openings further
apart to help invade new tissue [95] (Figure 7). Fibers of the cytoskeleton conduct electrons
from the negative centrosome near the nucleus to the positively charged outer plasma cell
membrane surface side as radical negatively charged electrons to provide polymerization
chemistry for advancing actin fibers [3]. Electrons conducted through microtubules to actin
fibers [96] are generated in excess by mitochondria under irregular oxidative conditions with
hypoxia [3]. Actin has shown reorganization during exposure to free radicals from H2O2 that
increase cell movement [97]. In terms of free-radical initiation, H2O2 has been shown to be
excellent for polymerizing polyester resins [98]. By analogous ROS free-radical chemistry,
oxidized low density lipids have demonstrated the ability to produce actin polymerization in
macrophages [99]. Of great concern, H2O2 with other ROS are found in many cancer cells
[3,69–77,100].
Metastatic cancer cells have a lower modulus (or less stiffness approximately) to deform
more easily than normal cells and also show pleomorphic smaller sizes with less membrane
area [101–103]. Cell modulus increases with actin fiber cytoskeleton organization, but in
cancer actin fibers become disordered where cells become less stiff and more easily distort
[103]. Conversely, tumor tissue density increases as a risk factor in cancer [40,104–106].
Higher tissue density reflects greater amounts of extracellular matrix collagen [40,104],
collagen crosslinking [42,45], and increasing stiffness [42,45] to provide increased traction
for cancer cell focal adhesions that improve cell motility [106,107]. Stiffer tumor substrata
found in higher density fibrotic areas with increased collagen promote ROS at the cancer
cell membrane to activate the EMT for cancer cells during tumor metastasis [43]. Also, cells
tend to move toward stiffer substrates of higher modulus [107]. Stiffer collagen tissue would
interfere with O2 diffusion to account for promoting ROS from associated mitochondria
nearby the hypoxia of the plasma membrane. Further, ROS response near the plasma
membrane in contact with increased fibrotic collagen should include creation of focal
adhesions at the leading edges to contract by free-radical covalent bonding that pull the cell
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forward toward the stiffer tumor tissue and better explain EMT cancer cell motility. By
possible relationship to ROS and EMT cancer cell movements, lysyl oxidase is an enzyme
that promotes extracellular matrix collagen crosslinking and stiffness [108–110] as a
hypoxia-related protein which is associated with cancer metastasis [41,111].
Atherosclerosis
Atherosclerosis known by “hardening of the arteries” is a foremost medical problem that
embodies extensive disease linked with high ischemic-related mortality [28,112–114].
Arterial stiffness appears to be associated with oxidative stress [115–119] and increased
extracellular matrix collagen deposition crosslinking [120]. In addition to advancing arterial
stiffening, atherosclerosis represents systemic pathology where lipids infiltrate into the
vessel walls with inflammation, cells and fibrotic scar tissue to produce appreciable
narrowing of the main susceptible arteries and the foundation for most cardiovascular
disease [112–114,121]. Further, from National Institutes of Health records by gross
pathology imaging, considerable lipid-rich solids can form to accumulate directly in a vessel
lumen [1] that suggests intense free-radical covalent chemistry is involved. Ischemia can
cause a heart attack with infarct or a stroke and brain damage when blood flow is interrupted
to the heart or brain, respectfully [36,112,113]. Free radicals attack carbon-carbon double
bonds in the alkene PUFAs that increase the risks for cardiovascular disease [122], while
ROS generated by mitochondria are considered an important part of the development for
atherosclerosis [28,36,121,123]. Further, alkanes form saturated solid fats by molecular
single bond rotation entanglements whereas planar alkene carbon-carbon double bonds
decrease molecular bond entanglements to form unsaturated oils [2,37,38,51,52]. Following
chronic free-radical buildup with oxidative cleavage of PUFAs at lower pH to produce
shorter reactive unsaturated lipid aldehyde crosslink products, reactive secondary sequence
carbon-carbon double-bond chain-growth PUFA polymerization might include a loose
interpenetrating network through the lipid core with other molecules like saturated lipids to
alter fluidity of normal structures [1].
Extracellular lipid “fatty streak” deposition with inflammatory oxidized low density lipid-
filled macrophage “foam cells” is the initial signal of atherosclerosis in coronaries for young
adults and children [36,112–114]. Extracellular lipid pools form to accumulate that stain as
esters amassed in both macrophages and the extracellular space [36]. Ester staining indicates
the presence of simple lipids as triglyceride-fatty acids rather than complex lipid ring
structured cholesterol [37]. During the development of atherosclerosis, endothelial oxidative
stress is related to free-radicals and ROS [112,123–125], low density lipids
[36,112,124,125], ischemia [125], inflammation [112,124,125], and infection [112,124,125].
Subsequent free radicals form through the mitochondria in periods of ischemia [9–16,112]
that can support atherosclerosis [126,127]. Also, free radicals oxidize low density lipids that
deposit in vessel walls [112,124], accumulate by neutrophiles during inflammation [128]
and occur with infection [129–131]. Further, free radicals build up in all layers of the
atherosclerotic wall [124]. The plaque central lipid core may also contain a crystalline lipid
following necrosis of the macrophage foam cells [36]. By possible related chemistry, a
crystalline lipid has been shown possible by free-radical unsaturated lipid crosslinking in
connection with nonpolar O2 accumulation near a nonpolar interface that might be compared
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to a cell membrane surface [1]. Thick fibrotic lipid-rich-core plaques subsequently diminish
O2 diffusion [36,112] that can speed up the production of mitochondrial free-radicals
through ischemia [9–16,112]. Reduced O2 transport could produce both excess
mitochondrial free radicals and acids that should be better acknowledged toward increasing
the build up of lipid pathology at all stages and forms of disease [1]. When free radicals
crosslink alkenes, subsequent oxygen diffusion is compromised even more to deeper inner
layers [132–135].
Lipid peroxyl free-radical products due to crosslinking by O2 that can generate a hard lipid
peroxidation crystalline-like material are a matter of more concern [1]. When harder lipid
peroxidation crystal formation develops even at the molecular level, O2 diffusion to deeper
layers would subsequently be even more restricted than with the rubbery gellation of
reactive secondary sequence carbon-carbon double-bond crosslinking [1]. Saturation of a
hydrocarbon polymer by removing carbon-carbon π double bonds and replacement with σ
single bonds interferes greatly with electron travel and also changes more polar surfaces
toward nonpolar [6,136] that needs some understanding for likeness between the weak
intermolecular forces of attraction [137]. Nonpolar O2 concentration could exaggerate at a
nonpolar insulating surface like nonpolar endothelial lipid cell membranes in an artery to
create a possible nonpolar insulating free-radical sequestering condition that could develop
with reactive lipid breakdown aldehyde acrolein crosslinking unsaturated lipids [1].
Increasing free radical concentrations then create the potential reaction circumstances for
both combined double-bond molecular oxygen lipid peroxidation into crystal structure also
with lipid alkene carbon-carbon double-bond reactive secondary sequence crosslinking into
a solid lipid gel-like polymer [1].
Diabetes
ROS are involved in the development of obesity or diabetes and further thought to promote
insulin resistance [138]. High oxidative damaged lipids and proteins are found in different
tissues of both type I and type II diabetes [138]. In type II diabetes mellitus the cell
membrane PUFA: saturated fatty acid ratio reduces with an increase in membrane stiffness
[52]. In addition to greater membrane rigidity by increased packing of saturated fatty acids
with loss of unsaturated fatty acid oils [2,51,52], covalent crosslinks need consideration
between carbon-carbon double bonds that pull molecules together at the molecular bond
level [2]. Since type II diabetes mellitus is associated with ROS [22,139], the PUFA:
saturated fatty acid ratio decrease with increased membrane stiffness [52] is also indicative
of free-radical carbon-carbon double bond breakdown with an initial loss of unsaturated
lipids and subsequent generation of lipid breakdown aldehydes that can produce percents of
highly reactive unsaturated aldehyde products [1]. Lower molecular weight reactive
unsaturated aldehydes then greatly promote free-radical carbon-carbon double bond reactive
secondary sequence chain growth crosslinking with covalent structural rigidity [1].
Crosslinked unsaturated lipid chain growth organization structure could subsequently be
apparent pathology chemistry for the increased membrane stiffness in type II diabetes
mellitus [2]. An important concern regarding the free-radical lipid crosslinked membranes
and lowered membrane fluidity would be to interfere with O2 diffusion [66–68] that could
then increase associated diseases [2].
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Reduced membrane fluidity can generate membrane interactions unfavorable for glucose
transport with increased insulin resistance [52]. Insulin resistance develops through a
complex manner in the cell membrane with multiple molecularly integrated network-type
steps that interplay for insulin signaling [138]. Physiologic lower ROS concentrations with
cell-signaling protein actions [30] might include molecular attractions favorable for insulin
function. Conversely, clinically potential high ROS concentrations could combine at several
levels to exacerbate diabetes and increase insulin resistance. As examples, lower membrane
fluidity interferes with molecular diffusion, possible uneven crosslinked surface membrane
irregularities with exposed lipid radicals might interfere with insulin membrane docking and
the total of damaging protein modifications collectively could then severely limit insulin
molecular performance at the outer plasma cell membrane.
Of particular pathologic alarm related to ROS associated with diabetes mellitus is the high
risk of cardiovascular diseases including complications from renal damage, microangiopathy
that causes blindness and heart attacks [139]. Increased membrane stiffness with reduced
deformability caused by ROS in erythrocytes [48,49,52] and increased stiffness with plasma
cell membranes of endothelial cells surrounding vessel walls [52] both of similar diameters
could possibly reduce capillary blood flow to tissues resulting in hypoxia, nutritional
deficiencies and microangiopathy [52]. Also, National Institutes of Health gross pathology
imaging shows that lipid-rich solids can form directly in a vessel lumen [1] that may suggest
concentrated free-radical crosslink chemistry to generate interference with blood flow at any
level. Further, ROS associated diabetic microangiopathy extends to the bone marrow and
may play a role in reducing hematopoietic stem cells that are needed for tissue repair and
differentiation particularly in ageing individuals with diabetes mellitus and ischemic
complexities [139]. Another severe complication of diabetes mellitus and secondary kidney
damage that promotes inflammation with an increase in ROS is diabetic neuropathy
[140,141].
Infection and Inflammation Responses
Infection or tissue damage can elicit an inflammatory response [142–146]. During
inflammation ROS are produced by the host cells to remove microorganisms [142–146].
Further, interruption of molecular oxygen at any level to mitochondria during energy
synthesis can increase the production of electrons from the electron transport chain
producing ROS and H2O2 [1–3,9–16,147]. Excess H2O2 that is not converted to water can
travel through cell membranes and generate ROS as HO [147]. In the extracellular space
ROS can produce damage to increase injury with increasing exaggerated immune responses
[142–145,147]. Conversely, as tissue damage proceeds the inflammatory response may not
control the infection to even promote invasive microorganisms deeper and expand initial
micropathology into more severe clinical manifestations or chronic complications [142–
145,147].
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Free-Radical Theory for Ageing Regarding Vitamins as Antioxidants and
Clinical Error
The Free-Radical Theory of Ageing asserts that ageing is due to the accumulation of free-
radical biologic damage which increases disease and death [19,20]. The chemical foundation
was thought to be a result of free radicals produced by mitochondrial oxidative proteins that
are enzymes through the energy synthesis process combined with the cation transition metal
catalysts in the connective tissue [19,20]. After generation free radicals reacted within cells
and tissues to begin the progression of ageing [19,20]. As one example, the accumulation of
oxidative damage is thought to play a significant role in creating mitochondrial degeneration
during ageing [9]. Consequently, the Free Radical Theory of Ageing indicated that treatment
could begin with antioxidants to safeguard cells and tissues from free radicals to reduce
ageing, increase lifetime and prevent disease [19,20]. Epidemiological research suggested
that nutrition especially by fruits and vegetables with an association to antioxidants could
prevent diseases and prolong life with vitamin A, β,β-carotene, vitamin E and vitamin C
recognized [148–161]. Age-related diseases considered for antioxidants most vulnerable to
ROS included cancers, cardiovascular disease, diabetes and neurological disorders
[36,138,150,155,158,160,161].
Because of the numerous nutrition research trials done on diets high in vegetables and fruit
demonstrating preventive improvements for disease, treatments for patients were regarded
on the foundation of potential vitamin antioxidant actions to offset the damaging properties
of ROS. Nevertheless, large vitamin clinical trials using supplements like vitamin A and β,β-
carotene, vitamin E or vitamin C or several combinations have not demonstrated successful
results in preventing cancer [161–169], cardiovascular disease [163,164,170–172] or
diabetes [138,173]. In fact, to much concern a β,β-carotene cancer prevention clinical study
that included 29,133 male smokers for an average of 6.1 years statistically significantly
increased risk of lung cancer 18% and overall mortality [162]. The higher mortality rate was
due to other pathology related to cardiovascular disease [162]. Another clinical trial that
examined a combination of β,β-carotene and vitamin A with smokers and asbestos-exposed
workers discovered a statistically significant 28% increase in lung cancer with the nutritional
supplementation and 17% increase in total mortality that required the clinical study to
conclude 21 months earlier than intended [164].
Despite the disappointing outcomes of the clinical trials with vitamin supplements, since
diets high in fruits and vegetables with vitamin A and vitamin E lowered risks for cancer and
cardiovascular disease, positive antioxidant properties may be related to nutrients other than
vitamins not yet recognized [161]. Similar recommendations for diabetes emphasize the
need for vitamins supplied from natural food sources by a balanced diet with alarm for
potential harm from nutritional vitamin supplementation [138,173]. As an extremely
important problem, antioxidant results for covalent bond crosslinking by polymerization
shrinkage tests with vitamin A and β,β-carotene nutrition supplements both demonstrated
exceedingly strong oxidative reactions by generating solids from low-viscosity oils when
reacted with peroxide-derived free radicals [1] (Figure 4). Lowering analogous cell
membrane fatty acid oil fluidity would reduce oxygen diffusion [66–68] and eventually
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create increased production of cellular free radicals during mitochondrial energy synthesis
and related diseases with mitochondrial ROS pathology [2]. Immense inconsistencies
between vitamin antioxidant potentials and clinical failures are due to the fundamental
vitamin antioxidant tests using spectrophotometer methods [174–176]. Antioxidant
spectrophotometer tests are based on optical color changes [174–176] that are the result of
conjugated molecules adsorbing energy chiefly by bond stretching or bending and electrons
moving to a higher-energy orbital [177] that is not an equivalent measure of biologic
covalent bonding. Conversely, covalent bonds generated by reactive secondary sequence
chemistry for oils as unsaturated oleic and linoleic fatty acid lipids (Figures 2 and 3), or
vitamin A and β,β-carotene (Figure 4), that all produced rubbery solid gels or also a possible
peroxidation crystalline lipid by molecular oxygen crosslinking (Figure 3) create a more
accurate foundation for all major ROS pathology. In addition, free-radical reactive secondary
sequence covalent chemistry or possible lipid peroxidation expose key failures in laboratory
vitamin tests that inaccurately influenced the disappointing vitamin A and β,β-carotene
clinical trials [1].
Free-Radical Inhibitor Hydroquinone
Important antioxidant properties of fruits and vegetables may be derived from compounds
other than vitamins not yet known [138,161]. The most familiar antioxidants for ROS are
recognized as the enzyme cellular proteins superoxide dismutases, catalase and glutathione
peroxidase [31,78,79,80] and can further include protein chains and peptide bonds that can
delocalize radicals [2,3]. Also, coenzyme Q10/ubiquinone is a small molecule that carries
electrons through the inner mitochondrial membrane in the electron transport chain which
has been accepted as an antioxidant and so utilized as an over-the-counter nutritional
supplement [178]. Additional quinones are developed for use in dermatology, food
preservatives, and as antioxidants to safeguard chemicals in polymer manufacturing.
Hydroquinone is utilized as a reducing agent, antioxidant, free-radical inhibitor for
polymerization, food preservative and nonprescription skin lightener to treat hyper-
pigmentation [179].
Hydroquinone epidemiological studies in a manufacturing plant with 9040 workers with an
equivalent 94,524 survival years over about a 10-year period showed statistically significant
decreases in mortality when evaluating exposed workers to both non-exposed plant workers
and the common population [179,180]. The identical worker exposure study further showed
statistically significant reductions in cancer rates, ischemic cardiovascular and
cerebrovascular diseases, respiratory diseases and digestive diseases when evaluating state
and national vital statistics [179,180]. An additional broad epidemiology study by 858 men
with specific hydroquinone exposure for 22,895 person-years at another manufacturing plant
for 48 years with an average contact of 13.7 years showed statistically significant decreases
in mortality and cancer rates when evaluating both non-exposed plant workers and the
common population [181,182]. More human exposure studies at a manufacturing plant with
significant levels of hydroquinone dust contact demonstrated no systemic toxicity [179,183].
Vitamin E α-tocopherol compared to hydroquinone (Figure 8), has some molecular
resemblance to hydroquinone with an aromatic hydroxyl group that greatly increases
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aromatic reactivity to possibly perform as an antioxidant. But, the aromatic ring for vitamin
E is fully substituted with molecular groups. On the other hand, hydroquinone has four
unsubstituted aromatic positions that can efficiently be activated toward ortho positions by
two para substituent hydroxyl groups for reactivity with a strong electrophile as a free
radical [184]. Two hydroquinone hydroxyl substituents must donate electrons by resonance
stabilization to the aromatic ring so that electrons can flow from the oxygen lone pair
electrons to add negative charges on the ring at the four possible open ortho positions for the
hydroquinone molecule [184]. Consequently, electrophilic aromatic substitution reactions
with hydroquinone or p-dihydroxybenzene would seem to be the main antioxidant chemistry
to scavenge free-radical electrophiles [2]. Further, vitamin E α-tocopherol is a great deal
larger hydrophobic or nonpolar molecule than hydroquinone and through laboratory
observations is virtually insoluble in water while hydroquinone has solubility to easily
diffuse through water [2].
To compare the covalent-bond reaction for antioxidant properties between vitamin E and
free-radical inhibitor hydroquinone, an unsaturated lipid and crosslinking unsaturated
reactive aldehyde acrolein mixture were combined with the Fenton redox couples benzoyl
peroxide initiator 4 wt% and cation transition metal cobalt naphthenate accelerator 4wt% to
create free radicals [1]. For evaluations, equal control groups were combined with different
weight percents of either vitamin E ((±)-α-tocopherol) or hydroquinone [1]. Polymerization
shrinkage was then measured over a period of 50 hours by quantifying the differences
between the original levels for the lipid reactant mixture volumes with the volumetric
shrinkage polymerization levels as a comparative measure of covalent bond crosslinking.
Results for hydroquinone demonstrated remarkable statistically significant increased
antioxidant properties for removing free radicals with reductions in polymerization
shrinkage during 50-hours of testing from the 28.2% control at 0.0wt% down to 11.6% at
7.3wt% (
p
<0.0001) (Figure 9). Antioxidant comparisons demonstrated an enormous
statistical significant increase in free-radical inhibition for 7.3wt% hydroquinone over 7.3wt
% vitamin E that showed virtually no antioxidant activity in scavenging free radicals by
polymerization shrinkage measurements of 27.8% after 50 hours, (
p
<0.00001).
Hydroquinone and vitamin E are compared simultaneously at 7.3wt% each in Figure 10.
Nonetheless, vitamin E appears to have beneficial properties other than as an antioxidant, for
example as a viscosity reducer [1,2].
Conclusions
Free radicals generated under mitochondrial oxidative stress are associated with excess
production of electrons and acid. Combined acid and free radicals with appropriate enzymes
can break unsaturated lipids down into reactive unsaturated aldehydes of lower molecular
weight. Subsequent reactive unsaturated aldehydes can then greatly help crosslink carbon-
carbon double bonds by a reactive secondary sequence free-radical chain growth
polymerization and even crosslink with O2 to form crystalline lipid peroxidation products.
Crosslinking decreases the respective fluidity of lipids or even forms solid structure that
reduces or blocks O2 diffusion. Subsequent lower O2 diffusion to mitochondria during
energy synthesis increases more generation of free radicals and acids in possible continuing
vicious cycles toward creating or maintaining most pathology known to mankind. Free
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radicals are also associated with crosslinking proteins and collagen to stiffen the
extracellular matrix in much pathology. Most importantly, hydroquinone, a free-radical
inhibitor designed to efficiently sequester free radicals, is a potential pharmaceutical for
medical treatment.
Acknowledgments
Support in part from National Institutes of Health Grant T32DE014300.
Abbreviations
O2Molecular Oxygen
ROS Reactive Oxygen Species
O2•− Superoxide Anion
H2O2Hydrogen Peroxide
HOHydroxyl Radical
PUFAS Polyunsaturated Fatty Acids
EMT Epithelial-Mesenchymal Transition
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Figure 1.
O2 is needed at the end of the electron transport chain in removing electrons and protons to
form H2O. (Molecular Biology of the Cell. 4th edition. Electron-Transport Chains and Their
Proton Pumps. Figure 14–26. Copyright © 2002, Bruce Alberts, Alexander Johnson, Julian
Lewis, Martin Raff, Keith Roberts, and Peter Walter; Available from: http://
www.ncbi.nlm.nih.gov/books/NBK26904/).
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Figure 2.
(A) Unsaturated fatty acid lipid oils, benzoyl peroxide free-radical initiator, cobalt
naphthenate transition metal accelerator and α,β-unsaturated aldehyde reactive lipid
breakdown product acrolein crosslinker polymerized into solid rubbery gel. (B) Unsaturated
fatty acid oils, benzoyl peroxide and cobalt naphthenate accelerator remain unreacted low-
viscosity oil without acrolein crosslinker. (C) Unsaturated fatty acid lipid oils, benzoyl
peroxide, and acrolein α-β unsaturated aldehyde remain unreacted low-viscosity oil without
cobalt metal free-radical accelerator. (Micromechanics/Electron Interactions for Advanced
Biomedical Research, 2011, Chapter 16. Free Radical Reactive Secondary Sequence Lipid
Chain-Lengthening Pathologies. Figure 10. Richard Petersen and Uday Vaidya).
Petersen et al. Page 23
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Figure 3.
Differences between free-radical polymerized reaction products for lipid peroxidation across
oxygen-oxygen double bonds and unsaturated lipid reactive secondary sequence
polymerization along carbon-carbon double bonds. (A) Reactive secondary sequence free-
radical polymerization with crosslinker and unsaturated lipids form solid rubbery gel on the
bottom. Crystalline polymerization lipid peroxidation products were pulled off the sides of
the reaction container that concentrated alongside of the nonpolar polyethylene container
surface. (B) Left Side-crystalline lipid peroxidation polymerization products of acrolein
crosslinked lipids and O2 and Right Side-reactive secondary sequence polymerized
unsaturated lipids in a solid rubbery gel phase. (Micromechanics/Electron Interactions for
Advanced Biomedical Research, 2011, Chapter 16. Free Radical Reactive Secondary
Sequence Lipid Chain-Lengthening Pathologies. Figure 12. Richard Petersen and Uday
Vaidya).
Petersen et al. Page 24
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Figure 4.
Free-radical polymerization of vitamin supplements containing numerous multiple
unsaturated carbon-carbon double bonds and without acrolein crosslinker generates rubbery
solid gels from low viscosity oils. (A) β,β-carotene. (B). Vitamin A (Micromechanics/
Electron Interactions for Advanced Biomedical Research, 2011, Chapter 16. Free Radical
Reactive Secondary Sequence Lipid Chain-Lengthening Pathologies. Figure 16. Richard
Petersen and Uday Vaidya).
Petersen et al. Page 25
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Figure 5.
Cell cultures from human connective tissue 500× (A) Normal cells with smoother membrane
borders. (B) Cancer cells with more spike-like protrusions revealing more irregular deeper
plasma cell membrane invaginations. (With permission from the National Institutes of
Health/Department of Health and Human Services).
Petersen et al. Page 26
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Figure 6.
Scanning electron microscopy of an isolated cancer cell with membrane ruffling and long
lamellipodia spike-like extensions. (With permission from the National Institutes of Health/
Department of Health and Human Services).
Petersen et al. Page 27
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Figure 7.
Metastasis scanning electron micrograph of a low modulus cancer cell moving through an
artificial hole showing stiff pseudopodia extensions called lamellipodia. (With permission
from the National Institutes of Health/Department of Health and Human Services).
Petersen et al. Page 28
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Figure 8.
Molecular structures for vitamin E (top) compared to hydroquinone (bottom).
Petersen et al. Page 29
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Figure 9.
Unsaturated lipid and reactive acrolein free-radical covalent bonding polymerization
shrinkage with hydroquinone free-radical inhibitor at different concentrations. (International
Research Journal of Pure & Applied Chemistry 2(4): 247–285, 2012, Reactive Secondary
Sequence Oxidative Pathology Polymer Model and Antioxidant Tests. Figure 15. Richard
Petersen).
Petersen et al. Page 30
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Figure 10.
Unsaturated lipid and reactive acrolein free-radical covalent bonding polymerization
shrinkage comparing antioxidant free-radical sequestering with 7.3wt% hydroquinone and
7.3wt% vitamin E. (
p
<0.00001 at 50hrs) (International Research Journal of Pure & Applied
Chemistry 2(4): 247–285, 2012, Reactive Secondary Sequence Oxidative Pathology
Polymer Model and Antioxidant Tests. Figure 16. Richard Petersen).
Petersen et al. Page 31
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... F-actin lies beneath the plasma cell membrane that supplies high modulus intracellular fiber structural support to increase cell stiffness [124][125][126], However, tight gingival intercellular junctions were suppressed increasingly on rough surfaces where f-actin did not disassemble to allow pliable cell spreading [123]. Conversely, f-actin disappeared in the areas of cell membrane lamellipodia extension development on smooth surfaces to allow high levels of filipodia formation with tight junctional epithelium and no intercellular gaps [123]. ...
... Conversely, f-actin disappeared in the areas of cell membrane lamellipodia extension development on smooth surfaces to allow high levels of filipodia formation with tight junctional epithelium and no intercellular gaps [123]. Subsequent filipodia are small membrane focal adhesion proteins thought to provide cell mobility by bond formation with bond contractions at the leading edge of the cell [124][125][126]. ...
... Normal cells have relatively smoother more-even round membranes with smooth nuclei compared to cancer cells that reflect free-radical oxidative stress with uneven distorted borders, membrane ruffling and irregularly shaped nuclei [124][125][126]. As a possible related interest, in cancer cells f-actin also disassembles intracellularly under the plasma cell membrane to create a highly pliable cell with low modulus that can squeeze between narrow gaps like openings in the blood vessel endothelium [124][125][126]. ...
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... In aerobic organisms, oxygen free radicals launch autocatalytic reactions that finally damage the living cell. The unsaturated carbon-carbon double bonds in the exposed end groups are particularly sensitive to free radicals forming a covalent single bond at a carbon atom to form a free radical at the opposite carbon atom [22]. Free radicals interact with molecular cross-linking for increased structural organization by reducing the transport of oxygen. ...
... Free radicals formed by limited O 2 can damage lipids and proteins and greatly increase molecular sizes in growing vicious cycles to reduce oxygen availability even more for mitochondria during energy synthesis. Further, at adequate free-radical concentrations a reactive crosslinking unsaturated aldehyde lipid breakdown product can significantly support free-radical polymerization of lipid oils into rubbery gel-like solids and eventually even produce a crystalline lipid peroxidation with the double bond of O 2[158]. ...
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