Introduction
Definition
Redox homeostasis, redox stress, and oxidative stress
I | Excess O2 (oxygen therapy) |
II
| Absorption of radiant energy (ultraviolet light) or ionizing radiation (radiotherapy) |
III
| Exposure to toxins: carbon tetrachloride, dioxin, alloxan and streptozotocin to name just a few |
IV
| Reduction-oxidation (redox) reactions during normal physiologic processes (cellular respiration) |
A. Respiratory chain enzymes and oxygen | |
B. Xanthine oxidase | |
C. Cytochrome P450 monooxygenase activity | |
D. NAD(P)H / NADH oxidase | |
E. Fenton reaction: Fe++ + H2O2 → Fe+++ + OH + OH- | |
F. Haber-Weiss Reaction H2O2 + O2- → -OH
-
+ O2 +OH- | |
V
| Ischemia – Ischemia reperfusion injury |
VI
| Inflammatory processes. Acute and chronic |
VII
| Once free ROS radicals form, they can react with membrane lipids, proteins and nucleic acid to initiate auto-catalytic reactions (ROS beget ROS) [9] |
Nicotinamide adenine dinucleotide reduced (NADH)
|
NADH Oxidase NADH / NAD
+
(mitochondrion, cytosol)
|
NADH + 2O2 → NAD+ + H+ + 2O
2
-
(Super Oxide) |
Nicotinamide adenine dinucleotide phosphate reduced (NAD(P)H)
|
NAD(P)H Oxidase NAD(P)H / NAD(P)
+
(membrane)
|
NAD(P)H + 2O2 → NAD(P)+ + H+ + 2O
2
-
(Super Oxide) |
Super oxide dismutase (SOD):
|
MnSOD = Mitochondrial SOD |
CuZnSOD = Intracellular (cytosolic) SOD |
EcSOD = Extracellular SOD |
O2- + SOD → H2O2 (hydrogen peroxide) |
Fenton Reaction: H2O2 + Fe++ → -OH' (the hydroxyl radical) * + Fe+++ + OH- |
Haber-Weiss Reaction: H2O2 + O2- → -OH
-
(the hydroxyl radical) + O2 +OH- |
Peroxynitrite: origins of reactive nitrogen species (RNS)
|
O2- is consumed. Nitric oxide (NO) is also consumed in this process with the creation of reactive nitrogen species (RNS). |
O2- +NO → ONOO- (peroxynitrite) + tyrosine → nitrotyrosine |
O2- +NO → ONOO- (peroxynitrite) + arginine → nitroarginine |
Nitroarginine competes for arginine in the formation of eNO. |
Nitrotyrosine reflects redox stress and leaves an indelible measurable footprint. |
A-FLIGHT toxicities | ||
---|---|---|
A
| Amylin (hyperamylinemia)/amyloid toxicity | ROS |
Ang II (also induces PKC) | ROS | |
AGEs/AFEs (advanced glycosylation/fructosylation endproducts) | ROS | |
Antioxidant reserve compromised | ROS | |
Absence of antioxidant network | ROS | |
Ageing | ROS | |
Angiogenesis (induced redox stress) Arteriogenesis (impaired PAI-1) | ROS | |
Atherosclerosis – Atheroscleropathy. [ROS beget ROS] | ROS | |
F
| Free fatty acid toxicity | ROS |
L
| Lipotoxicity | ROS |
I
| Insulin toxicity (hyperinsulinemia-hyperproinsulinemia) (endogenous) | ROS |
Inflammation toxicity | ROS | |
G
| Glucotoxicity (compounds peripheral insulin resistance) reductive stress Sorbitol / polyol pathway | ROS plus |
Pseudohypoxia (NADH/NAD increased) | PKC | |
H
| Hypertension toxicity | ROS |
t homocysteine toxicity | ROS | |
T
| Triglyceride toxicity | ROS |
A-DINNER | |
---|---|
A
| ATHEROSCLEROPATHY. ANGIOGENESIS (induced). ARTERIOGENESIS (impaired). |
D
| DERMOPATHY: Diabetic Scleroderma – Stiff skin, vulcanization of collagen (cross-linking). Necrobiosis Lipoidica Diabeticorum. Brown sunken atrophic scars anterior shin of legs (impaired scar formation associated with increased levels of PAI-I and impaired injury remodeling). |
I
| INTIMOPATHY. INTIMAL REDOX STRESS. Macro vascular plus micro vascular vasa vasorum angiogenesis with intraplaque hemorrhage → Coronary Events. |
N
| NEPHROPATHY. Microvascular. |
N
| NEUROPATHY. Microvascular. Overriding sympathetic stimulation pro vasoconstrictive. |
E
| ENTEROPATHY. Delayed gastric emptying. |
R
| RETINOPATHY. Microvascular. |
Metabolic syndrome and insulin resistance
I. | The insulin resistance syndrome |
II.
| Syndrome X |
III.
| Reaven syndrome |
IV.
| Metabolic syndrome (preferred term by WHO) |
V.
| Metabolic syndrome X |
VI.
| Multiple metabolic syndrome |
VII.
| Plurimetabolic syndrome |
VIII.
| Dysmetabolic syndrome |
IX.
| Cardiovascular dysmetabolic syndrome |
X.
| Cardiometabolic syndrome |
XI.
| The "H" phenomenon |
XII.
| The "Deadly quartet" |
I. | Strong family history of diabetes mellitus. |
II.
| High risk ethnic background (Aboriginal, Asian, Pacific Islander, Hispanic, African American, Native American Indian). |
III.
| Obesity (visceral, omental). Phenotypic changes of abdominal obesity: waist/hip ratio equal or greter than 1 in males and equal or greter than 0.8 in females. |
IV.
| Gestational diabetes. |
V.
| Macrosomia. |
VI.
| Multiparity. |
VII.
| Polycystic ovary syndrome (PCOS). |
VIII
| Impaired glucose tolerance. Two-hour postprandial blood sugar ranging from 140 to 199 mg/dL after 75 gram OGTT |
IX.
| Impaired fasting glucose : 110–125 mg/dL. |
X.
| Aging. |
XI.
| Hypertension. |
XII.
| Dyslipidemia. The lipid triad (increased VLDL, triglycerides, small dense LDL. Decreased HDL). |
The manifold – A-FLIGHT toxicities
(A). Angiotensin II toxicity
(A). Advanced glycosylation endproducts: AGE
(A). Antioxidant enzymes
Antioxidant reserve compromised
Absence of network antioxidant enzymes
eNOS
Other antioxidant enzymes
Enzymatic antioxidants |
SUPER OXIDE DISMUTASE (SOD) – Location: mitochondrion |
[O2- + SOD → H2O2 + O2] |
ecSOD (extracellular) |
MnSOD (mitochondrial) |
CuZnSOD (intracellular) |
CATALASE – Location: peroxisome |
[2H2O2 + catalase → 2 H2O + O2] |
GLUTATHIONE PEROXIDASE – Location: mitochondrion/cytosol |
(Glutamyl-cysteinyl-glycine tripeptide) glutathione reduced -SH to the oxidized disulfide GSSG. |
(Glutathione peroxidase) [GSH + 2H2O2 → GSSG + H2O + O2] |
(Glutathione reductase) [GSSG → GSH] at the expense of [NADH → NAD+] and/or [NAD(P)H → NAD(P)+] |
* NOS (nitric oxide synthase). – Location: membrane |
Isoforms: |
(e) NOS (endothelial): good (importance of eNOS uncoupling) LDL native and oxidized.
|
(n)NOS (neuronal): good |
(i)NOS (inducible-inflammatory): good in host defense. BAD in chronic inflammation. |
O2- and nitric oxide (NO) are consumed in this process with the creation of reactive nitrogen species (RNS). |
O2- + NO → ONOO- (peroxynitrite) + tyrosine → nitrotyrosine. (also causes eNOS uncoupling) |
Nitrotyrosine reflects redox stress and leaves a measurable footprint. |
NO: the good; O2-: the bad; ONOO-: the ugly [122] |
eNOS uncoupling causes the generation of O2' instead of NO induced by LDL-C, Glucose, O2', and ONOO'.
|
Nonenzymatic antioxidants
|
URIC ACID
|
VITAMIN A
|
VITAMIN C
|
VITAMIN E
|
THIOLS
|
APOPROTEINS: Ceruloplasmin and transferrin. Bind copper and iron in forms which cannot participate in the Fenton reaction. [9] |
(A). Ageing
(A). Amylin toxicity
(A). Angiogenesis (accelerated): Arteriogenesis (impaired): Vascularization Paradox In T2DM
The process of Angiogenesis starts with capillaries and ends with more capillaries
The process of arteriogenesis starts with small arterioles and ends with larger arterioles
(A). Atherosclerosis and atheroscleropathy
(F). Free fatty acids
L). Lipotoxicity – generalized
(L). Lipotoxicity – specific
I). Insulin toxicity
(I). Inflammation toxicity
Rubor
Calor
Dolor
Tumor
Redox stress and inflamation. (figure 6)
(G). Glucotoxicity
I. |
LATENT STAGE:
[EARLY]
|
Insulin Resistance:
| |
• Genetic Component | |
• Environmental component. Modifiable: obesity/sedentary life style. Nonmodifiable: aging. | |
Beta Cell Defect: (Dysfunction) | |
• Genetic ....... Abnormal processing, storage or secretion. | |
• Intracellular/extracellular amylin fibril toxicity. Abnormal processing, storage or secretion. | |
Intra-Islet Endothelial Absorptive Defect:
| |
• Heparan sulfate proteoglycan (HSPG) PERLECAN of the capillary endothelial cells avidly attracts amylin (IAPP) and the islet amyloid forms an envelope around the capillary. This is in addition to the increase in the basement membrane associated with the pseudohypoxia (associated with glucotoxicity) and the redox stress within the capillary. | |
II.
|
TRANSITION STAGE:
[MIDDLE]
|
Persistent Hyperinsulinemia
| |
Persistent Hyperamylanemia
| |
• Continued remodeling of the endocrine pancreas (amyloid). | |
• Beta cell displacement, dysfunction, mass reduction and diffusion barrier. | |
III.
| IGT STAGE (Impaired Glucose Tolerance): [LATE] "Pre-diabetes" Human Health Services (HHS) and American Diabetes Association (ADA) term. |
[Start treatment at this time]
| |
[Diagnose earlier: rejuvenation of the 2 hour glucose tolerance blood sugar 140–199 mg/dL]
| |
• Increased insulin resistance [Feeds forward] > Glucotoxicity [Feeds forward] > Insulin resistance [Feeds forward] > Glucotoxicity: creating a vicious cycle. | |
• Islet amyloid. Increasing beta cell defect. Loss of beta cell mass with displacement. (Remodeling of islet architecture including extracellular matrix). Beta cell loss centrally. | |
IV.
| IFG STAGE (Impaired Fasting Glucose): [LATER] "Pre-diabetes" Human Health Services (HHS) and American Diabetes Association (ADA) term. |
[Blood sugar ranging 110–126 mg/dL]
| |
[Impaired hepatic glucose production]
| |
• Increasing global insulin resistance (hepatic) with subsequent gluconeogenesis. Feeding forward in the vicious cycle to accelerate insulin resistance globally. | |
V.
|
OVERT STAGE:
[TO LATE]
|
[50% loss of beta cell function]
| |
Va, Vb, Vc. Phases I, II, III: mild, moderate/severe, complete. Use medications that do not increase insulin or amylin. Use combination therapy. Start treatment at stage III-IV (IGT-IFG). | |
• Paradigm Shift. Start treatment at the earlier stage of IGT. |
R | Reductase inhibitors (HMG-CoA). Decreasing modified LDL cholesterol, i.e. oxidized, acetylated LDL cholesterol. Improving endothelial cell dysfunction. Thus, decreasing the oxidative stress to the arterial vessel wall and the islet. Redox stress reduction. |
A
| ACEi-prils. ARBS-sartans. Both inhibiting the effect of angiotensin-II locally as well as systemically. Affecting hemodynamic stress through their antihypertensive effect as well as the deleterious effects of angiotensin II on cells at the local level – injurious stimuli. Decreasing the A-FLIGHT toxicities. Plus the direct/indirect antioxidant effect within the islet and the arterial vessel wall. Redox stress reduction. |
Aspirin antiplatelet, anti-inflammatory effect. | |
A
| Aggressive control of diabetes. Decreasing modified LDL cholesterol, i.e. glycated LDL cholesterol. Improving endothelial cell dysfunction. Also decreasing glucose toxicity and the redox stress to the intima and pancreatic islet. Aggressive control of Hcy with folic acid with its associated additional positive effect on re-coupling of the BH4 cofactor with the eNOS reaction to produce eNO. Redox stress reduction. |
S
| Statins. Improving plaque stability (pleiotropic effects) independent of cholesterol lowering. Improving endothelial cell dysfunction and preventing the angiogenesis associated with arterial vascular remodeling which destabilizes the unstable atherosclerotic plaque. Plus, the direct/indirect antioxidant anti-inflammatory effects within the islet and the arterial vessel wall promoting stabilization of the unstable, vulnerable islet and the arterial vessel wall. Style: Lifestyle modification: Stop smoking, lose weight, exercise, and change eating habits. Redox stress reduction |