Summary Molecular Pathophysiology
Table of Contents
Atherosclerosis ........................................................................................................................ 2
Aortic Aneurysms ................................................................................................................... 3
Cholesterol ............................................................................................................................... 5
Apoptosis ................................................................................................................................. 6
Ubiquitination and Disease.................................................................................................... 8
Obesity and Insulin Resistance .......................................................................................... 10
Proposed underlying mechanisms of Insulin Resistance .........................................................12
Selective versus Total Insulin Resistance: A Pathogenic Paradox .........................................13
Isoprenoid Biosynthesis ...................................................................................................... 13
Biogenesis Disorders ........................................................................................................... 15
Phenylketonuria .............................................................................................................................15
Zellweger syndrome ......................................................................................................................15
Lysosomes ............................................................................................................................ 17
Regulation intracellular cycling and nutrient supply ................................................................17
Biogenesis of lysosomes ...............................................................................................................18
M6P receptors ........................................................................................................................................ 18
Lysosomal storage disorders (LSD) .................................................................................. 19
Therapy............................................................................................................................................21
Medical Yeasts and Virulence ........................................................................................... 21
Design of novel antifungal drugs ....................................................................................... 23
Drugs, smells and colors: Glucuronyltransferase in health and disease ....................... 24
© 2014 REB Morpurgo
,Atherosclerosis
Atherosclerosis is the underlying pathology of myocardial and cerebral infarction.
Atherosclerosis is a vascular disease and is the narrowing of the lumen of the blood
vessel.
The activation of endothelial cells results in an increase in white blood cells in the
area. High levels of LDL in the blood, leads eventually to the oxidation of LDL to
oxLDL and is taken up by macrophages in the blood vessel cell wall. This causes the
formation of foam cells, which activate cytokines and growth factors. These cytokines
and growth factors enhance the growth of the smooth muscle cells and results in the
formation of a plaque. A plaque can result in disturbed blood circulation.
Atherosclerosis is a multi-factorial disease:
Environment, can be treated via prevention:
o Smoking
o Diet
o Lack of exercise
Risk factors:
o High LDL (LDL) - treated with statins
o Low HDL
o High blood pressure - various drugs on the market
o Diabetes - treated with insulin
Genetic components:
o Familiar Hypercholesterolemia
o Tangier disease
Genetic predisposition is due to multiple genes.
The rupture of a plaque results in local clot formation. The immune system delivers
proteases and prothrombotic factors, which leads to the formation of a thrombus or
clot.
The four cells involved in Atherosclerosis are:
T cells
Monocytes/Macrophages
Endothelial cells
Smooth muscle cells
Treatment of Atherosclerosis can occur through angioplasty and the placement of
stents. In angioplasty a catheter is inserted and blown up into a balloon at the place of
the lesion to facilitate widening of the blood vessel. In some cases stents are placed
where the blowing of the balloon occurs, to ensure widening of the vessel. Stents are a
metal frame, which is inserted into the artery to widen the artery. This results in better
blood circulation, which is declined through atherosclerosis. There are different kinds
of stents:
Bare-metal stents
Drug-eluting stents
© 2014 REB Morpurgo
, The treatment via bare-metal stents can result in in-stent restenosis - in which smooth
muscle cell proliferate through the stent. By using drug-eluting stents the proliferation
of smooth muscle cells is inhibited by mTOR enhanced expression of p27Kip1, which
is a cell cycle inhibitor. These drugs inhibit the growth of all cells.
Nur77 is a nuclear receptor and transcription factor, which inhibits smooth muscle
cell growth. Nur77 is an interesting target for in-stent restenosis. Nur77 inhibits
endothelial cell activation: immune cells do not travel to the area and cannot become
foam cells.
Testing the genome for SNPs can identify patients with an increased risk for in-stent
restenosis. p27kip1 -838A identifies individuals with a lower risk for in-stent
restenosis.
Aortic Aneurysms
Aneurysm is the widening of the lumen of the blood vessels. Different types of aortic
aneurysms:
Abdominal aortic aneurysm (AAA)
Ascending aortic aneurysm
Descending aortic aneurysm
Aortic arch aneurysm
Risk factors AAA:
Age (>50)
Gender (>M)
Smoking positively influences AAA
Family history
Atherosclerosis
Adventitia: Fibroblasts
Media: Smooth muscle cells
Intima: Endothelial cells
Lumen: red and white blood cells
Atherosclerosis is a disease of the intima, which results in a
narrowing of the lumen and an increase in intima through plaque
forming.
Aneurysm is a disease of the Media and Adventitia.
Aneurysm is a result from excessive wall
© 2014 REB Morpurgo
Table of Contents
Atherosclerosis ........................................................................................................................ 2
Aortic Aneurysms ................................................................................................................... 3
Cholesterol ............................................................................................................................... 5
Apoptosis ................................................................................................................................. 6
Ubiquitination and Disease.................................................................................................... 8
Obesity and Insulin Resistance .......................................................................................... 10
Proposed underlying mechanisms of Insulin Resistance .........................................................12
Selective versus Total Insulin Resistance: A Pathogenic Paradox .........................................13
Isoprenoid Biosynthesis ...................................................................................................... 13
Biogenesis Disorders ........................................................................................................... 15
Phenylketonuria .............................................................................................................................15
Zellweger syndrome ......................................................................................................................15
Lysosomes ............................................................................................................................ 17
Regulation intracellular cycling and nutrient supply ................................................................17
Biogenesis of lysosomes ...............................................................................................................18
M6P receptors ........................................................................................................................................ 18
Lysosomal storage disorders (LSD) .................................................................................. 19
Therapy............................................................................................................................................21
Medical Yeasts and Virulence ........................................................................................... 21
Design of novel antifungal drugs ....................................................................................... 23
Drugs, smells and colors: Glucuronyltransferase in health and disease ....................... 24
© 2014 REB Morpurgo
,Atherosclerosis
Atherosclerosis is the underlying pathology of myocardial and cerebral infarction.
Atherosclerosis is a vascular disease and is the narrowing of the lumen of the blood
vessel.
The activation of endothelial cells results in an increase in white blood cells in the
area. High levels of LDL in the blood, leads eventually to the oxidation of LDL to
oxLDL and is taken up by macrophages in the blood vessel cell wall. This causes the
formation of foam cells, which activate cytokines and growth factors. These cytokines
and growth factors enhance the growth of the smooth muscle cells and results in the
formation of a plaque. A plaque can result in disturbed blood circulation.
Atherosclerosis is a multi-factorial disease:
Environment, can be treated via prevention:
o Smoking
o Diet
o Lack of exercise
Risk factors:
o High LDL (LDL) - treated with statins
o Low HDL
o High blood pressure - various drugs on the market
o Diabetes - treated with insulin
Genetic components:
o Familiar Hypercholesterolemia
o Tangier disease
Genetic predisposition is due to multiple genes.
The rupture of a plaque results in local clot formation. The immune system delivers
proteases and prothrombotic factors, which leads to the formation of a thrombus or
clot.
The four cells involved in Atherosclerosis are:
T cells
Monocytes/Macrophages
Endothelial cells
Smooth muscle cells
Treatment of Atherosclerosis can occur through angioplasty and the placement of
stents. In angioplasty a catheter is inserted and blown up into a balloon at the place of
the lesion to facilitate widening of the blood vessel. In some cases stents are placed
where the blowing of the balloon occurs, to ensure widening of the vessel. Stents are a
metal frame, which is inserted into the artery to widen the artery. This results in better
blood circulation, which is declined through atherosclerosis. There are different kinds
of stents:
Bare-metal stents
Drug-eluting stents
© 2014 REB Morpurgo
, The treatment via bare-metal stents can result in in-stent restenosis - in which smooth
muscle cell proliferate through the stent. By using drug-eluting stents the proliferation
of smooth muscle cells is inhibited by mTOR enhanced expression of p27Kip1, which
is a cell cycle inhibitor. These drugs inhibit the growth of all cells.
Nur77 is a nuclear receptor and transcription factor, which inhibits smooth muscle
cell growth. Nur77 is an interesting target for in-stent restenosis. Nur77 inhibits
endothelial cell activation: immune cells do not travel to the area and cannot become
foam cells.
Testing the genome for SNPs can identify patients with an increased risk for in-stent
restenosis. p27kip1 -838A identifies individuals with a lower risk for in-stent
restenosis.
Aortic Aneurysms
Aneurysm is the widening of the lumen of the blood vessels. Different types of aortic
aneurysms:
Abdominal aortic aneurysm (AAA)
Ascending aortic aneurysm
Descending aortic aneurysm
Aortic arch aneurysm
Risk factors AAA:
Age (>50)
Gender (>M)
Smoking positively influences AAA
Family history
Atherosclerosis
Adventitia: Fibroblasts
Media: Smooth muscle cells
Intima: Endothelial cells
Lumen: red and white blood cells
Atherosclerosis is a disease of the intima, which results in a
narrowing of the lumen and an increase in intima through plaque
forming.
Aneurysm is a disease of the Media and Adventitia.
Aneurysm is a result from excessive wall
© 2014 REB Morpurgo
