Updated (version 0.9) Pathology;5 Chronic-Diseases Root-causes (Series; Complexity Theory, 3D Perspective, Author ''HABIB'')-Ver 0.9.pdf

Ver 0.9 Sep. 5th 2022 HABIB’s Complexity 3D Perspective
Eng Emad Farag HABIB
Pathology: The Five Chronic Diseases.
Molecular Pathology
Top Five Chronic Diseases
& Risk-Factors
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VERSION 0.9 , September 5th 2022
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TOC:
* Five Chronic Diseases Causes 60% of total Death Cases worldwide
* Two Main (Molecular) Risk-Factors : are the Root-cause of the 5 Diseases
1. Oxidants : [ Normal Oxidants / Abnormal Oxidants ]
( Reactive Oxygen Species (ROS), AntiOxidant Defenses (AOD), Oxidative Stress Index (OSI) )
1a. Inflammation : Normal Inflammation / Abnormal Inflammation
( Acute versus “Chronic” Inflammation )
2. DNA Damage : [ Normal DNA Alterations / Abnormal DNA Damage ]
( Repairable versus Irreparable Damaged-DNA : DDR System )
The Big Picture: Interlinks : on the way to Chronic Diseases !:
( More Details )

TOC:
( More Details )

Eng. Emad Farag HABIB
Five Chronic Diseases Causes 60% of total Death Cases worldwide
Cancer : Malignant Tumors
CVD : CardioVascular Diseases
COPD : Chronic obstructive pulmonary disease
DM : Diabetes Mellitus
AD : Alzheimer's Disease
Anti-oxidants, Anti-Inflammatory, Cytotoxic,
Insulin, Alleviation, Cytostatic, … , …
are Examplary Benefits of Medications & Pharmaceuticals.

Pathology: Top Five Chronic Diseases : Ver 0.9 Sep. 5th 2022 Eng Emad Farag HABIB
HABIB’s Complexity 3D Perspective
• Two Main (Molecular) Risk-Factors : are the Root-cause of the a/m 5 Diseases :
• Free Radicals:
• (Bad) Free Radicals act progressively to cause damage to many body cells.
• Such damage can be avoided by :
• The Dietary Intake of AntiOxidants ( in an appropriate quantities )
• DNA Damage:
• (Bad) DNA Damage means that many body cells have reached a critical phase of “Permanent
Damage”
• Such damage can be avoided by :
• The Regular-followup of “Chronic” Health Problem(s) ( via remedial Medications )
• The Immediate-response to any “Acute” Health Problem ( via seeking Medical Help )
Next Slides will show how such damages initiate & proceed
( aka: the Pathology of Chronic Diseases ) …

Marginal
Redox Signaling
Bad Inflammation
Ref: LibreTexts, : Paradox
Good Inflammation
Ref: Paradox
Good Free Radicals Bad Free Radicals
Good Gene-Expression
Regulation
Ref:net
Compromised Gene-
Expression Regulation
Regulating
Mechanisms
Free
Radicals
Inflammation
DNA
Damage
Pathology: The Top Five Chronic Diseases: [Cancer, CVD, COPD, DM, and AD] :
With Two Main Root-Causes : [ Free Radicals & DNA Mutations ] . (in addition to “Chronic Inflammation”) .
Simplified “Big-Picture Outline-Diagram” // Main Reference: https://doi.org/10.1111/bph.14888
NORMAL Cell
(Cell State :
Restored/ Adapted)
Marginal
DNA Damage
Marginal
Inflammation
Mitochondrial
DNA Damage
(6 Features)
Cellular DNA
Damage
(6 Features)
(DNA Damage-based) Pathologies
(Inflammation-based) Pathologies
(FreeRadical-based) Pathologies
Five
Chronic
Diseases
REDOX Pathology
Inflammation Pathology
DNA Pathology
(Normal State) (Regulators) ( Combined Stresses Pathologies) (~Disease)
(Abnormal State) (Stress-Responses Marginal-Efficacy) ( Hallmarks )
Pathological
Interactions
Main
Functions
Affected
The 2 main Root-causes:
Free Radicals,
and DNA Damage
( in addition to Inflammation)

Redox System : ( Reduction-Oxidation):
Summary:
Reactive Species ( e.g. Reactive Oxygen Species “ROS” ) are the well-known products of the Process of
Metabolism within the body. These Products are well regulated to keep them within limits, but in case of
Increased Exposure to Oxidative agents or suffering major health problems: ROS levels within the body are
largely increased . Meanwhile : Body AntiOxidant Enzyme systems have a limited capacity in tackling such
abnormal situation, resulting in an overall unbalanced “Oxidative Stress” (OS), which represents a true health
threat when it exceeds certain limits . Luckily-enough OS can easily be evaluated via a Simple “MDA Serum
Level” test, which is a reliable Indicator to such marginal condition.
Details:
ROS: Reactive Oxygen Species (ROS) : Increases with increasing stress (cf 5 stress-types).
AO: The AntiOxidant (AO) Enzymes: are able to ( Neutralize) the Oxidants : but they have only a limited
capacity of Neutralization, as they reach some (Maximum or Saturation or Depletion ) level : and such
Saturation means an overall resultant of ( Oxidative Stress ) .
DRUGS: This a/m Physiological Limitation : emphasizes the importance of Medications and Drugs to mitigate
any Oxidative Stress(es) As-much-as-possible As-early-as-possible. Relevant Medication(s) have the potential
to effectively tackle the most-stressful physiological conditions like: infection, inflammation, injury, chronic
conditions, .. .
MDA: is a reliable Indicator of “Oxidative Stress”
( Noting that: next-slides’ MDA values are “Normalized” : MDA serum level, in micrograms per liter (mcg/L) : Reference : research paper
“Targeting oxidative stress in disease” , Forman et al, 2021, doi.org/10.1038/s41573-021-00267-5 )

Redox System : Levels of “Oxidative Stress” ( OS ) :
Oxidative Stress : 5 levels :
Also: the MDA serum level, in micrograms per liter, (mcg/L), as a reliable
indicator :
1: Normal Oxidative level .
2: Oxidative Stress .
3: Oxidative system Challenged .
4: Pathologies .
5: Disease .
The Battle between : Oxidants & AntiOxidants

0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
1 2 3 4 5
Serum
MDA,
(mcg/l),
normalized
( Increasing Oxidative Stress)
1=Normal, 2=Stress, 3=Challenged, 4=Pathologies, 5=Disease
Oxidative Stress, AntiOxidant Saturation,
MDA Indicator
Oxidants
AntiOxidant
Oxidative Stress/ Hence MDA
Antioxidants
Oxidants
1
2
3
4
1
2
Redox System
(Possible Levels)
5
Main Problem is : ”Limited-Capacity” of ”The AntiOxidant Enzymes”
Oxidants AntiOxidant
Oxidative Stress/ Hence
MDA Redox Signalling #
1.7 0.8 0.9 Normal 1
2.1 1 1.1 Stress 2
2.5 1 1.5 Challenged 3
3 1 2 Pathologies 4
4 1 3 Disease 5

0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
1 2 3 4 5
Serum
MDA,
(mcg/l),
normalized
MDA Indicator
Oxidants
AntiOxidant
Antioxidants
Oxidants
1
2
3
4
1
2
Redox System
(Possible Levels)
5
#1 of 5: Normal Physiology: Full homeostasis: OS ( & MDA) are within range.
( noting that: Oxidant themselves also act as secondary messengers, to activate antioxidants)
1.7 0.8 0.9 Normal 1
2.1 1 1.1 Stress 2
3 1 2 Pathologies 4
4 1 3 Disease 5

0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
1 2 3 4 5
Serum
MDA,
(mcg/l),
normalized
MDA Indicator
Oxidants
AntiOxidant
Antioxidants
Oxidants
1
2
3
4
1
2
Redox System
(Possible Levels)
5
#2 of 5: Perturbation Physiology: Oxidative Stress: Adaptive homeostasis,
( System is able to stimulate a Redox Signalling , despite no damage yet : via a Change of system Parameters,
to boost the antioxidant defenses : in response to a “mild elevation” in ROS )
1.7 0.8 0.9 Normal 1
2.1 1 1.1 Stress 2
3 1 2 Pathologies 4
4 1 3 Disease 5

0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
1 2 3 4 5
Serum
MDA,
(mcg/l),
normalized
MDA Indicator
Oxidants
AntiOxidant
Antioxidants
Oxidants
1
2
3
4
1
2
Redox System
(Possible Levels)
5
#3 of 5: Oxidative System Challenged : Saturated AntiOxidant System
( System is still able to stimulate a Redox Signalling : via a stress-inducible Enzymatic-Activation, exceeding the
baseline activation, but the AntiOxidant reaches its Saturation level “AntiOxidant Depletion” ).
1.7 0.8 0.9 Normal 1
2.1 1 1.1 Stress 2
3 1 2 Pathologies 4
4 1 3 Disease 5

0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
1 2 3 4 5
Serum
MDA,
(mcg/l),
normalized
MDA Indicator
Oxidants
AntiOxidant
Antioxidants
Oxidants
1
2
3
4
1
2
Redox System
(Possible Levels)
5
#4 of 5: Pathologies : damage to macromolecules .
( Pathologies : damage to macromolecules : However : system is mainly able to prevent potential production of
the most harmful substances: peroxynitrite (oNoo−) and hydroxyl radical (•OH) )
1.7 0.8 0.9 Normal 1
2.1 1 1.1 Stress 2
3 1 2 Pathologies 4
4 1 3 Disease 5

0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
1 2 3 4 5
Serum
MDA,
(mcg/l),
normalized
MDA Indicator
Oxidants
AntiOxidant
Antioxidants
Oxidants
1
2
3
4
1
2
Redox System
(Possible Levels)
5
#5 of 5: Disease : Aberrant Redox Signalling
( hence system suffers potential damages )
1.7 0.8 0.9 Normal 1
2.1 1 1.1 Stress 2
3 1 2 Pathologies 4
4 1 3 Disease 5
Aberrant Redox Signalling

0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
1 2 3 4 5
Serum
MDA,
(mcg/l),
normalized
MDA Indicator
Oxidants
AntiOxidant
Antioxidants
Oxidants
1
2
3
4
1
2
Redox System
(Possible Levels)
5
Main Problem is : The ”Limited-Capacity” of the “AntiOxidant Enzymes”
( leading eventually to Aberrant Signalling )
1.7 0.8 0.9 Normal 1
2.1 1 1.1 Stress 2
3 1 2 Pathologies 4
4 1 3 Disease 5

Risk Factors & Interactions (Titles & Details Outline-Diagram)
REDOX Biology: Redox Levels Summarized
( Neutral)
(Redox Interactions) :
ROS Levels, Relevant (Redox Signalling & Features), AO & Stress Levels
Oxidative Stress, Oxidative Challenge / AntiOxidant (AO) Defense, Redox Signalling / Oxidative Damage , …
Oxidative Stress
System Challenged
Pathologies
(Physiology): Normal Fluctuations,
No Damage.
Disease ..
ROS Level Redox (Hence) (Resulting) Pathologies Homeostasis Notes
Signalling AO Level Stress Levels
Regulated, Specific, and Brief
1 1
2
ΔSubstrates  Δ Enzymes
Regulated, Specific, and Brief
3
4
Regulated, Specific, and
Prolonged (counter-damage)
2
2
Unregulated, Non-specific, and
Random?
2
Aberrant, Non-specific, and
Chronic?
2
5
(Physiology): Abnormal Stress
Tackled, No Damage.
(Physiology): Damage (mostly tackled) ,
AO (Saturated)
Pathologies: Damage,
AO (Saturated)
Pathologies: DNA Damage,
AO (Saturated),
Disease Initiation?...
Adaptive homeostasis
(Change of system Parameters)
Normal homeostasis
(~Fixed Parameters)
~Saturated homeostasis
disruption of redox homeostasis,
disruption of redox homeostasis
oxidants act as secondary messengers
Stimulation of redox signalling without any damage.
Transient alteration of redox homeostasis and redox
signalling  elevated antioxidant defenses.
Enzymes Activation: [ baseline / stress-inducible ] /
Coordination of Ezymes Activation / till reaching
Saturation of the AntiOxidant enzyme system.
a/m damage, plus: generation and removal of
[superoxide (o2•−), H2o2 and nitric oxide (•NO) ] Are
out of limits : allowing significant production Of
peroxynitrite (oNoo−) and hydroxyl radical (•OH) : 2
pathologies [ more oxidative damage (Progressive) /
Aberrant Redox Signalling ]
(more) oxidants : damage to macromolecules (non-
enzymatically ) / But still: (only negligible) production
Of peroxynitrite (oNoo−) and hydroxyl radical (•OH)
Antioxidants
Oxidants
1
2
3
4
1
2
Redox System
(Possible Levels)
5
Oxidants & AntiOxidants: Levels details:

0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
1 2 3 4 5
Serum
MDA,
(mcg/l),
normalized
MDA Indicator
Oxidants
AntiOxidant
So :
2 Recommended “Remedial Actions” based on OS level :
If Your Oxidative Stress ( or
MDA) level is Here :
You must
Reduce Stress
If Your Oxidative Stress ( or
MDA) level is Here :
You must
Take More
AntiOxidants

Oxidants: ( Production – Damage ):
Summary:
Types / normal products of metabolism / even-more: useful ( excess anti-oxidants: can be bad) / Abnormal ROS
Details:
ROS: Reactive Oxygen Species

Anti-Oxidants
• Anti-Oxidants : works via 3 Means :
– Scavenging Reactive Species
– Inducing Endogenous Antioxidant
– Inhibiting the Production of ROS/RNS
• (i) by scavenging reactive species
• due to an elevated reactivity (measured as a rate constant)
• that allows it to scavenge oxidants
• before they can affect other biological targets such as nucleic acids and proteins;
• (ii) by inducing endogenous antioxidant responses
• through Nrf2-dependent gene expression
• to modulate the pathophysiological and physiological outcomes of oxidant exposure [96];
• (iii) by inhibiting the production of ROS/RNS
• either by inhibiting the expression or activities of enzymes
• such as NADPH oxidases or xanthine oxidase, inhibiting inflammation
• or by decreasing mitochondrial electron leaking [97].

• “INFLAMMATION” Definition :
• Inflammation is commonly considered as a complex reaction in vascularized connective tissues, in
response to exogenous and endogenous stimuli.
• The ultimate goal of this protective response is to rid the organism of both the initial cause of cell injury and
the consequences of such injury.
• However, exaggerated or unregulated prolonged inflammatory process can induce tissue damage and is the
cause for many chronic diseases
• Sequence of The “INFLAMMATION” Process :
• Summary :
( read the next sequence from End to Start ! )
• Chronic Inflammation  Inflammation  tissue damage and oxidative stress  ( Enzymes, RXS, mediators ) 
Activation  Migration [adhesion molecules, receptors, chemokines ]  infiltration (substances)  [ Injury /
Infection ]  (initial cause)
• Details :
(exaggerated or unregulated prolonged inflammatory process ) : tissue damage and oxidative stress
 release of [many enzymes / reactive species / and chemical mediators ] ( by activated inflammatory cells: At the
site of inflammation )
 Cells Activation
 Migration.Details : [ margination, rolling, and adhesion of leukocytes to the vascular endothelium //
transmigration across the endothelium // and migration toward a chemotactic stimulus ]
 Migration of : [neutrophils, monocytes, and lymphocytes ] Cells
 Luekocytes Migration to the site ( the source of stimulus )
 infiltration : adhesion molecules + (their respective receptors and chemokines of leukocytes )
 Consequences
 Initial Cause of Inflammation: [ Tissue Injury or Infection ]

• Acute vs Chronic Inflammation :
•Chronic inflammation arises in the following settings:
• [ Persistent infections / • Hypersensitivity diseases. / • Prolonged exposure to potentially toxic agents / • Some
(special) forms of chronic inflammation ]
Links to : diseases (not inflammatory disorders) : such as Alzheimer disease, metabolic syndrome and the
associated type 2 diabetes, and certain cancers : in which inflammatory reactions promote tumor development.
•• Persistent infections by microorganisms that are difficult to eradicate, such as mycobacteria and certain viruses, fungi, and parasites.
These organisms often evoke an immune reaction called delayed-type hypersensitivity (Chapter 5). The inflammatory response sometimes
takes a specific pattern called granulomatous inflammation (discussed later). In other cases, unresolved acute inflammation evolves into
chronic inflammation, such as when an acute bacterial infection of the lung progresses to a chronic lung abscess.
•• Hypersensitivity diseases. Chronic inflammation plays an important role in a group of diseases that are caused by excessive and
inappropriate activation of the immune system (Chapter 5). In autoimmune diseases, self (auto) antigens evoke a self-perpetuating immune
reaction that results in chronic inflammation and tissue damage; examples of such diseases are rheumatoid arthritis and multiple sclerosis.
In allergic diseases, chronic inflammation is the result of excessive immune responses against common environmental substances, as in
bronchial asthma. Because these autoimmune and allergic reactions are triggered against antigens that are normally harmless, the
reactions serve no useful purpose and only cause disease. Such diseases may show morphologic patterns of mixed acute and chronic
inflammation because they are characterized by repeated bouts of inflammation. Fibrosis may dominate the late stages.
•• Prolonged exposure to potentially toxic agents, either exogenous or endogenous. An example of an exoge-
•nous agent is particulate silica, a nondegradable inanimate material that, when inhaled for prolonged periods,
•results in an inflammatory lung disease called silicosis (Chapter 13). Atherosclerosis (Chapter 10) is a chronic
•inflammatory process affecting the arterial wall that is thought to be induced, at least in part, by excessive
•production and tissue deposition of endogenous cholesterol and other lipids.
•• Some forms of chronic inflammation may be important in the pathogenesis of diseases that are not conventionally thought of as
inflammatory disorders. These include neurodegenerative diseases such as Alzheimer disease, metabolic syndrome and the associated
type 2 diabetes, and certain cancers in which inflammatory reactions promote tumor development. The role of inflammation in these
conditions is discussed in the relevant chapters.

DNA: ( Normal Alterations– Aberrant
Damage )
DNA Structure :
DNA is made up of a double helix of two complementary strands. The double helix
describes the appearance of a double-stranded DNA which is thus composed of two
linear strands that run opposite to each other and twist together to form.
DNA Replication :
During replication, these strands are separated. Each strand of the original DNA
molecule then serves as a template for the production of its counterpart, a process
referred to as semiconservative replication. As a result of semi-conservative
replication, the new helix will be composed of an original DNA strand as well as a
newly synthesized strand.[4] Cellular proofreading and error-checking mechanisms
ensure near perfect fidelity for DNA replication.
DNA Repair :
DNA repair is a collection of processes by which a cell identifies and corrects damage
to the DNA molecules that encode its genome. In human cells, both normal metabolic
activities and environmental factors such as radiation can cause DNA damage,
resulting in tens of thousands of individual molecular lesions per cell per day.Many of
these lesions cause structural damage to the DNA molecule and can alter or eliminate
the cell's ability to transcribe the gene that the affected DNA encodes.

DNA Damage Types :
[ Sequence/ EpiGenetic ] , (~Content/Context) ! :
• DNA Sequence Damage :
( DNA lesion: 9 types : Sorted by "INCIDENCE", i.e. rate of occurrence : (least probable) to (most probable) :
• DSB
• Cytosine deamination
• Cyclopurine adducts
• Depyrimidination
• 8-oxoG
• Malondialdehyde adducts
• Alkylation adducts
• Depurination
• SSB
• DNA EpiGenetic Damage :
• Methylation (Silencing) Pattern
• Histones
• Chromatin
• miRNA (Non-coding RNA)
• DNA Miscellaneous Damage :
• Genomic Instability Anti-oxidants, Anti-Inflammatory, Cytotoxic,

Marked Genes
Are a gtoup of “Special case
Genes” : that behave “counter-
intuitive” while Performing a DNA
repair process. These Genes
experience an (Increased activity
of the Gene) while the repair
process is ongoing .

TOC:
What do we Know so Far ?! [ Analytically / Descriptively ]
What Functions/Processes are Affected ? (~ 30 Function-Groups !! )
The Big Picture: How things Go Bad ? [ Normal/ Abnormal/ Regulatory-Mechanisms Marginalized!/ Pathologies]
Pathology : [ Stresses  2 Molecular Processes  Abnormalities & Aberrations  Alterations & Damages ]
The Good News: 2 Main Molecular Processes (ONLY) are of concern ! (Approximate Figurative Diagram)
Conclusion
Abbreviations / Terminology & Colors Clarification / References

Stresses:
cf slide 5 stresses
DNA Adducts (Non EpiGenetic) : 5 :
Double-strand breaks (DSBs)
ICL (Crosslinks)
SSBs, BM's (Single-strand breaks, Base Modifications)
Bulky Adducts
Erroneous insertions
DNA Damage DETECTION Hierarchy : 5 :
[ Sensors / Mediators/ Transducers/ Mediators/
Effectors]
DNA EpiGeneticAlterations (4 Components) :
Methylation/ Demethylation Pattern
Histones
Chromatin remodelling
miRNA (non-coding)
{ The 4 components: regulate gene expression in a
concerted way, with “DNA methylation” believed to be
crucial }
3 most active Free Radicals:
[ nitric oxide / peroxynitrites / lipid peroxidation]
3 critical-damage Pathways:
Oxygen (O2 •− and NO )
Nitration of Tyrosine
Hydroxyl free radical (OH• radical)
3 critical-damages to Bio-molecules:
nitric oxide
Peroxynitrites
lipid peroxidation
I don’t take any (Drugs, Narcotics, … ) !!!
Never Ever !
And I work under ( non-relenting MICROWAVE torture) +
DROWSY (Elida-machine) !! ( + Solvents in my home! )
ALCOHOL: Last time: more than 15 years ago (50ml wine
in family dinner) June 24th 2022
And This is a PURE Self & Lone study, for knowledge
benefit per se, in addition to possibly easing international
jobs, (not for EG marriage nor relationships at all).
More Specific: This a SELF study/research
Without ANY scientific or technical help at all
from anyone. PURE SELF STUDY 100% (July 2022)
Superoxide Dismutase Enzyme :
Is the Most Effective Enzyme counteracting the toxicity of
the a/m species.
Outcomes of the DNA-Damage Global-Response :
[ Repair / Tolerance / Apoptosis / Tumor / Senescence ]
Free Radicals + Inflammation : +ve Feedback Loop :
OS  NFκB  Cytokines, Chemokines  Inflammation
 ( more ROS production & AntiOxidant Depletion) 
OS  ..
IL-6  NOX4  ROS : ( which induces the +ve
Feedback loop by )  NOX4  IL-6 …
Features of the DNA-Damage Global-Response :
[ induction of multiple genes / cell cycle arrest / inhibition
of cell division ]
(OS + Inflammation + DNAD) : +ve Feedback Loop :
( Many such loops):
Cancer: Increased ROS Production: [ increased
metabolic activity of cancer cells / immune cells present
in the tumor micro-environment ]
The ROS-induced DNA base modification : induces
inflammation ( same a/m NFκB reaction, but with DNA
involved).
Mitochondria dysfunction  ROS ( Exported to nucleus)
Stress: Formation of “Stress Granule Assembly”
Ref: Paradox
Mitochondrial: Stress Response:
Motility: transport and movement
Fusion/fission: OMM, IMM
Inter-organellar contacts: ER-
Mitochondria, nanotunnels
Intra-Mitochondrial dynamics: Cristae
remodeling
Rebuilding and biogenisis: Changes in
mass/content
Recycling and permeabilization:
UPR(mt), MDVs, mitophagy, PTP
Cellular: Stress Response:
Intra/Inter-cellular signalling: Ca++, ROS,
peptides, CMG
Gene expression: biogenesis
Cell: (re)programming, (De-
)Differentiation
Quality Control: Autophagy
Senescence: Telomere erosion, SASP
Cell death: Apoptosis, necrosis
OS causes disease via one of 4 pathways. These are:
protein oxidation, DNA oxidation, lipid peroxidation and
oxidative modification of sugars (Paper Onset 2016US)
MDA: “Malondialdehyde” (MDA) , as an indicative of
Oxidative Stress (OS), Promising Researches .. .
(Normal) (Regulators) ( Combined Stresses Pathologies) (~Disease)
(Abnormal) (Stress-Responses Marginal-Efficacy) ( Hallmarks )
What do we Know so Far ?! [ Analytically / Descriptively ]
Functions/Processes:
Affected by a Disrupted REDOX System
( cf slide, ~30 Functions )
Antioxidant Systems:
[Enzymatic antioxidants / nonenzymatic antioxidants /
Plasma Proteins :3: (+metals) / Urea ? ] {paper paradox}
Five
Chronic
Diseases

What Functions/Processes are Affected ?
(~ 30 Function-Groups !! )
Apology:
For the
Error in this
slide :
in Ver 0.8
(20220713)
REDOX-Imbalance: Functions/Processes Affected
Main Fn #
ATP Production 1
Cell Fn(s)
ROS, OS, AntiOxidants Defenses (AOD) 2
Oxygen supply, hypoxia, respiration, lungs,, 3
Glucose, Insulin 4
Fats, Oils, Lipids in general 5
Proteins, aa / adipose tissues 6
Other Cell (metabolic) Functions 7
Cell Signalling, Signalling pathways 8
Tissue/Cell Processes/States:
Inflammation / Immune sys/ Host Defenses/ Allergy 9
Tissue (remodeliing) , Anchoring, Matrix, Adhesion, Migration / Cell Integrity, CytoSkeleton 10
Angiogenesis 11
Blood supply, Cardio, vascular, RBC, ../ Blood Supply 12
Lymph 13
Renal, … 14
Liver, Metabolism 15
Endocrine, Hormonal, … 16
Neurons, CNS, .. 17
Physical Fitness 18
Extreme Conditions/States: Starvation 19
Pediatrics, Neonatal, .. 20
Geriatrics, Aging, 21
Longterm Processes ( Cellular & Mitochondrial DNA ):
Stress_Adaptation 22
ER stress 23
Mt damage 24
DNA Alterations/Repair/Damage 25
Cell: Growth / Growth Factor?/ Megalo? ... 26
Cell: Proliferation/ Division(Mitosis)/ Differentiation 27
Cell: Fate: Healthy, Senescence, Tolerance, Apoptosis, Necrosis / Consequences 28
Cancer, Tumors, Malignant, Onco-, .. 29
Cancer Complications 30

Pathology :
[ Stresses 2 Molecular Processes Abnormalities & Aberrations Alterations & Damages Disease]
Interlinks : on the way to Chronic Diseases !
( a Simplified Diagram )
+ve Feedback Loop
(Bi-partite)
Free Radicals + Inflammation
Normal Physiological
Balances
& Homeostasis
Stresses
Redox
Signalling
Free Radicals
Inflammation
Oxidative
Stress
(OS)
+ve Feedback Loop
(Tri-partite)
OS +Inflammation +DNAD
Redox Signalling
System (Disrupted)
Inflammation
(Chronic)
Normal
DNA
Mutations
DNA
Alterations
DNA
Repair
AntiOxidants
Irreparable DNA
Alterations
Many Main
Functions/
Processes are
Affected/Altered
Mitochondrial
DNA Damage
(6 Features)
Cellular DNA
Damage
(6 Features)
Abnormal
DNA
Alterations
+ve Feedback Loop
(Bi-partite)
Stresses + DNA Mutations
(Normal) (Regulators) ( Combined Stresses Pathologies) ( Hallmarks )
(Abnormal) (Stress-Responses Marginal-Efficacy) (Permanent Alteration) (~Disease)
List of ~ 30
Functions/ Processes
(cf)
Five
Chronic
Diseases

List of ~ 30
Functions/ Processes
(cf)
+ve Feedback Loop
(Bi-partite)
Free Radicals + Inflammation
Normal Physiological
Balances
& Homeostasis
Stresses
Redox
Signalling
Free Radicals
Inflammation
Oxidative
Stress
(OS)
+ve Feedback Loop
(Tri-partite)
OS +Inflammation +DNAD
Redox Signalling
System (Disrupted)
Inflammation
(Chronic)
Normal
DNA
Mutations
DNA
Alterations
DNA
Repair
AntiOxidants
Irreparable DNA
Alterations
Many Main
Functions/
Processes are
Affected/Altered
Mitochondrial
DNA Damage
(6 Features)
Cellular DNA
Damage
(6 Features)
Abnormal
DNA
Alterations
+ve Feedback Loop
(Bi-partite)
Stresses + DNA Mutations
Five
Chronic
Diseases
The Good News: 2 Main Molecular Processes (ONLY) are of concern !
(Approximate Figurative Diagram)
Good News: Amid a myriad of Factors and Processes:
Including : Lifestyle, Stresses, Cellular & Organellar Damages,
Pathological Hallmarks and Diseases :
We have two pivotal factors that enjoy 3 important features:
1. Causality
2. Patient-managable
3. Biochemically-substantiated
( from a “Preventive Medicine” Perspective )

Complexity Theory
(Very Draft)
((   Chronic Disease   ))
Permanent ( Irreparable ) Damage
 DNA Wrong Mutation
 Pushing the smart ( Complexity Dynamics ) towards a Permanent (usuaul/Deteriorating)
Reaction
 the smart ( Complexity Dynamics ) is disturned to “attempt” usual
mutations/emergence ( by letting such mutations survive ).
 AOD Saturation
 ~Combined Stress
 ~Persistent Stress alongwith shortage in AOD (AntiOxidant Defense Enymes)

DNA Mutations
(Normal , Good )
Mutations
(Abnormal, Bad)
Mutations
DNA Adducts
(non-permanent)
Modifications, Crosslinks, strand breaks
Oxidative Damage
95% of Mitochondria Products are not
Active Species
DDR (Repair
Mechanism)
Successful Repair
Unsuccessful Repair
Cell Dynamics
& Stress Adaptation
Cell Unreparable
Damage
Damage is ~
“Bearable”?
Cell-Cycle Arrest
(Unreparable damage:)
( in Mutant Cells , Accumulated , ..)
Marginal
DNA Damage
Proliferative Pathway
Lipid Peroxidation
Protein Oxidation
Oxidative Stress
Aging
Abnormal
Aggregations
( Lipids, Proteins, via 4 pathways..: )
Aberrant
Cell-cycle
P53 << Wnt
P53 >> Wnt
Mutant Cell
Proliferation
Clonal Selectionof Apoptosis-resistant Cells
Cell Death
SENESCENCE
Non-Replicating
Cell ?
Brain, Muscle, Liver
Replicating
Cell ?
Stem Cell
Unbalanced ROS
[ unbalanced proinflammatory and anti-inflammatory
cytokine production ]
P53 Repair (~ 2nd )
Genomic Instability
And possible Chemotherapy resistance
Alternations can be handled?
Extent and Severity: Amount and type
can NOT be handled?
~Checkpoints
Survival-Response Network
Cell-cycle Arrested
Halted Temporarily ( for repair)
Increased Metabolic Activity
+ROS: by neutrophils &
macrophages ( @tumor micro-
environment)
Marginal
Inflammation
Marginal
Redox Signaling
CVD
Cancer
Neuro-
Degenerative
Disease, AD
~Risk Factors ~Pathologies Disease
COPD
{over} Permeability of
Capillaries
{over} Accumulation of
MΦ & Leukocytes
{over} ROS
Production
{over} Proteases
at site
{over} Lysosomes
at site
sustained inflammation
Chronic Inflammation : Prolonged & Increased : Tissue
Injury & ROS Production
Redox Signaling
System
(disrupted)
Re: ibreText, : Paradoxs
Permeability of
Capillaries
Accumulation of
MΦ & Leukocytes
MΦ & Leukocytes
to Site
Proteases
to site
Lysosomes
to site
Blood Clot
Acute Inflammation : Beneficial for Tackling : Injury and/or Infection
Collagen
Tissue Repair
/ Pathogen
Elimination
Ref: Paradox
RNS
Cell Signalling
(enzymes and transcription)
Reactive Chlorine
Species
ROS
Chronic Diseases
( against malfunctioning cells)
Normal ROS: as Bi-products of Metabolism / are utilized against:
Pathogens & Chronic Diseases
Pathogen
Elimination
Mitochondria
dysfunction
Proteins, lipids,
and DNA
Harmful ROS : Affecting/Damaging:
Molecules, Cell Organelles, and Membrane
Nitration of Tyrosine
Hydroxyl free radical
(OH• radical)
Oxygen (O2 •− and
NO )
Cellular
Metabolism
Marginal
DEGENERATION
Marginal
CARCINOGENESIS
Tumor Suppressor Genes
are Hypermethylated
Oncogenes and Pro-metastatic
Genes
are hypomethylated
Inactive Genes:
Methylation =
Scilencing
Cell Development
and Growth
Inactive Genes”
Demethylation =
Activate
Active Genes:
Regulatory Regions
Cell Replication
Intact DNA : Normal Cell Functions: Genes’ Expression is Regulated
Normal Cell Functions,
Adaptation
Ref:net
Repair
Cell Cycle
Arrest
Stress
Response
Damaged DNA : Survival-Response Network :
EpiGenetic Alterations
Ex: Methylation-Demethylation Pattern
Aberrations
Stresses
DNA Adducts
( Sequence )
Tissue Injury
, - membrane fluidity, ,
+ membrane leakiness
,damage membrane
proteins,
thereby inactivating : receptors, enzymes, and ion
channels
Normal Cell Functions: Produce RXS :
Types of Reactive (X) Species (RXS) :
(Over)Reactive Species :
( 3 Pathways)
DNA Damage Repair (DDR)
Stress Response
Apoptotic Pathway
mucus hypersecretion
membrane lipid peroxidation
mitochondrial respiration affected
alveolar epithelial injury
remodelling of extracellular matrix
alveolar epithelial apoptosis
oxidative inactivation of antiproteases and surfactants
parenchymal cells: aberrant DNA methylation patterns
hypermethylated: key stress-response pathways
Differentially Methylated Regions(DMRs):
in airway fibroblasts
parenchymal fibroblasts
DM (T2D)
Inflammation & Vascular Complications
hyperglycaemia
ROS & OS
Excessive Release of FA release from adipose tissue
Insulin Resistance
hyperglycaemia  (auto-oxidation of glucose)
stimulation of hexosamine pathway flux 
(Excessive, More) ROS & OS
high proliferation of SMC & Adhesion Molecules:
(Protection Gene “Erα” : PromoterRegion : CpG island )
High levels of oxidized lipids : damaged blood vessels,
macrophage activation, formation of foam cell
(lipid-containing)
Lipid & Protein Oxidation
microglial cells (macrophage-like cells in the brain)
interact with the beta-amyloid proteins : and build up in
neurons , subsequently producing inflammatory
cytokines and free radicals : that destroy the neurons
ROS levels : increases with Age
loss of mitochondrial function
altered Metal Homeostasis
Decrease in Global DNA methylation :
[ temporal cortex, frontal cortex and hippocampus ]
Gene SILENCING: of: tumor suppressor genes:
Gene ACTIVATION: of: oncogenes and pro-metastatic
genes
Free
Radicals
Inflammation
DNA
Damage
reduced Antioxidant Defense
impairment in Synaptic Activity and Neurotransmission
in the Brain
Cognitive Dysfunction
increased ROS due to increased metabolic activity of
cancer cells
increased ROS produced by NADPH oxidases that are
activated by cancer-related signalling pathways
ROS released by neutrophils and macrophages
present in the tumor micro-environment
OS : activates transcription factors : inflammation and
immune response
ROS: damage of biomolecules such as DNA, RNA,
lipids and proteins
alterations in Antioxidant Defense and DNA Repair
Mechanisms
Increased mitochondrial oxidative stress
and generation of excessive ROS
NADPH oxidases
inhaled oxidants : increases ROS
(produced in airways epithelial cells)
reduced methylation : promoter region of IL6:
inflammation cascade: More cytokines
(from macrophages)
… Affecting :
Healing Objectives : Which Necessitates Recruiting
Substances & Cells to Site :
Chronic Inflammation Means : … Causing :
Regulated Gene-Expression: For : Regulated Gene-Expression: Via : DNA Pathology : 3 Systems are Involved:
The Big Picture: How things Go Bad ?
[ Normal/ Abnormal/ Regulatory-Mechanisms Marginalized!/ Pathologies]
Tissue Injury
NORMAL Cell
(Cell State :
Restored/ Adapted)
Mitochondrial: Stress Response:
Motility: transport and movement
Fusion/fission: OMM, IMM
Inter-organellar contacts: ER-Mitochondria,
nanotunnels
Intra-Mitochondrial dynamics: Cristae remodeling
Rebuilding and biogenisis: Changes in
mass/content
Recycling and permeabilization: UPR(mt), MDVs,
mitophagy, PTP
Cellular: Stress Response:
Intra/Inter-cellualr signalling: Ca++, ROS, peptides,
CMG
Gene expression: biogenesis
Cell: (re)programming, (De-)Differentiation
Quality Control: Autophagy
Senescence: Telomere erosion, SASP
Cell death: Apoptosis, necrosis
DNA oxidation
Sugar oxidative
modification

Simple Conclusion : Don’t “COMBINE” Risk Factors ! :
“ .. The key to Disease Prevention
is to eliminate as many of the causes of OS {Oxidative Stress} as is possible,
for it is the TOTAL OS
from whatever source(s) that causes Disease Onset .. “
( doi: 10.1515/intox-2016-0006 : research paper “MDA” 2016USA)
STRESS:
Stresses
5: Extrinsic to Intrinsic :
[ Infections / Environmental ( incl Physical & Chemical) / BioChemical / Metabolic/ Genetic ]
Details:
Infections: Viruses, bacteria
Environmental: Toxins, chemotherapy, UV, mechanical, ETC inhibitors
BioChemical: Calcium and iron overload, oxidative stress
Metabolic: Substrate deprivation or oversupply
Genetic: mtDNA mutations/deletions, nDNA mutations
STRESSES & Life Style : the known 4 stress-management practices of:
[ suitable exercise / rest / appropriate nutrition / awareness of stress ]
Conclusion

Conclusion
Simple Conclusion : Don’t “COMBINE” Risk Factors ! :
MEDICATIONS & DRUGS:
The Antioxidants Limitation of the Redox System : emphasizes the importance of MEDICATIONS and DRUGS in mitigating
Oxidative Stress(es) and their causes (cf) . If you are already suffering from any CHRONIC disease: The Regular intake of
your medications can help in controlling the disease and in avoiding any complications . If you are encountered with any
NEW [ inflammation/ infection/ injury ] : Immediately consult your Physician to get the appropriate treatment.
2 Notes: [ Extra ANTIOXIDANTS = Useless ! / avoiding “CHRONIC” Exposure ]
A reasonable Intake Quantities of ANTIOXIDANTS, in either natural or pharmaceutical form : provides a good protection
against Free Radicals threats. However, keep in mind that an “extra” intake of antioxidants won’t do you any good:
regarding a “Protective Medicine” context : Adequate intake simply aims at avoiding Deficiency of antioxidants.
Another good news: in that the human body can easily withstand acute stresses (but not chronic ones), which means that
being keen on avoiding any ( prolonged ) exposure to ( high stresses ) is quite enough to avoid most harmful consequences
.
Both Information Fragments: ( Extra = useless, and acute vs chronic ) : are related to the Enzymatic Nature of the
AntiOxidants Defenses (AOD): Where these defenses are functioning via some “Enzymatic” mechanism, rather than via the
AntiOxidant Substrates themselves …
Life-span & CALORIC Restriction.(CR) : “… is the most successful intervention to extend lifespan and/or health
span … “
Micro-preventative MEASURES
[+diet , antioxidant / -water disinfection products / -meats / -preservatives / -toxins / -exercising (pollution) / -plastics / -
pharmaceutical / -obesity / +medical help ] . ( note: this is a brief & temp list, for more elaboration from its good source)

Abbreviations :
Abbreviations:
ROS Reactive Oxygen Species
AOD AntiOxidant Defenses
OS Oxidative Stress
REDOX: Reduction-Oxidation
RNS
RCS
RXS !:
ETC Electron Transport Chain
MDA
DNA
nDNA
mtDNA
miRNA
DDR DNA Damage Repair ( Mechanisms)
SSB Single-strand Break (in DNA)
DSB Double-strand Break (in DNA)
ICL Inter-strand? Cross-Links
BM Base Modification
ER Endoplasmic reticulum
AA Amino Acids
Abbreviations:
CVD : CardioVascular Diseases
COPD : Chronic obstructive pulmonary disease
DM : Diabetes Mellitus
T2D: Type 2 Diabetes ( DM is two types)
AD : Alzheimer's Disease
RBC Red Blood Cells
CNS Central Nervous System
UV Ultra Violet light (Radiation)
cf refer to

Terminology Clarification
• What is meant by “Root-cause” (here) ?
( in this review: “Root-cause” means : a Molecular “Patient-manageable causal factor” )
• “Root-cause” (in this context) means : a Molecular (Patient)-Manageable Causal Factor :
i.e. A factor/process that enjoys 3 important properties:
• #1: is a “CAUSE” ( or is located at an ~earlier point in a Causality-Cascade ),
• and #2: is a (Patient)-“MANAGABLE” factor ,
• and #3: is a MOLECULAR Factor (hence it is Biochemically-substantiated) .
( a/m 3 properties: conforms with the Personal “Preventive Medicine” perspective of this presentation )
• Who can benefit from this presentation ?
( This Presentation is useful to anyone having already basic knowledge of the basic notions,
and is seeking a “Structured Introductory Text” to the newly-discovered facts & interlinks ) :
• If you are already AWARE of some of the basic issues presented here :
i.e.: The Issues of : [ Redox, Inflammation, DNA Mutations, and Chronic Diseases ] ,
and if you are seeking a “structured” text
to introduce you to the recently-researched Molecular Pathology Links between :
the Molecular Processes of (Redox Biology and DNA Alterations) on one side,
and the Grand Pathological Hallmarks of (Chronic Diseases) on the other side .
• How this presentation is “Created” and “Edited” ?
• This Presentation is merely a ( self-study ) summary material, summarized while exploring and studying
the Subject ! , by selecting good ( Informative Material ) and putting it in PowerPoint Slides . Think of
this presentation as a ( Search Result ), that offers you some Quick Informative Material: Comparison
Tables, Illustrative Diagrams, and Structured-texts, rather than a coherent & planned (study-course) .
• You can benefit from this presentation mainly in getting the “Big Picture” of the Subject.

Coloring Clarification
The Following is just a re-stating / re-stressing: of some IMPORTANTN used Items/Sets :
i.e. Some “Set” = many “Items”: [ Degrees, Types, Levels, Dualities, .. ] :
• Degrees of OS :
• [ Normal Physiology/ Stress/ Challenged/ Pathologies/ Disease ] :
• Pathologies : [ Free-Radicals-based. Inflammation-based
and DNA-Damage-based ] :
• Anatomical Levels : [ Macromolecules, Organelles, … ] :
• Substantiality vs Complexity :
( Degree of Biochemical Substantiality ) versus ( Anatomical-Level or Hierarchical Complexity )
Oxidative Stress/
Hence MDA Redox Signalling #
1.7 0.8 0.9 Normal 1
2.1 1 1.1 Stress 2
3 1 2 Pathologies 4
4 1 3 Disease 5
Macro-molecules Cells Organism
Organelles Tissue, Organ, system Organism + LifeStyle

References:
1: Beetch et al, "Dietary Antioxidants Remodel DNA Methylation Patterns in Chronic Disease“ :
Megan Beetch, Sadaf Harandi-Zadeh, Kate Shen, Katarzyna Lubecka, David D. Kitts, Heather M. O'Hagan, Barbara
Stefanska : 2019 USA : https://doi.org/10.1111/bph.14888
2: wikipedia, DNA Replication : DNA Repair :
DNA replication – Wikipedia, 2022 ( June ). / Also: DNA repair - Wikipedia, 2022 ( June ).
3: Kaiser, MICROBIOLOGY (Inflammation) :
Gary Kaiser ( Community College of Baltimore County ) , LibreTexts , Microbiology ( Inflammation Section )
4: Roitt, Essential Immunology :
Ivan Roitt, 7th Edition , 1991
5: Zeliger , “Predicting Disease Onset in Clinically Healthy People”
Harold I. Zeliger , doi: 10.1515/intox-2016-0006 , ( MDA as a measure of total Oxidative Stress )
6: Forman et al, "Targeting Oxidative Stress in Disease: Promise and Limitations of Antioxidant Therapy“ :
Henry Jay Forman & Hongqiao Zhang , 13 July 2021, https://doi.org/10.1038/s41573-021-00267-5
7: Biswas, “Does the Interdependence between Oxidative Stress and Inflammation Explain the Antioxidant
Paradox?“ :
Subrata Kumar Biswas, 2016 , doi: 10.1155/2016/5698931
8: Wingate, “Medical Encyclopedia” :
Peter Wingate, The Penguin Medical Encyclopedia, 2nd Edition, 1985
9: Yousefzadeh, Henpita, et al. , "DNA damage—how and why we age?“ :
Matt Yousef zadeh†, Chathurika Henpita†, Rajesh Vyas, Carolina Soto-Palma,Paul Robbins, Laura Niedernhofer, 2021,
https://doi.org/10.7554/eLife.62852

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