"Live as if your were to die tomorrow' Learn as if you were to live forever'" Gandhi

1

• "Live as if your were to die tomorrow. Learn as
  if you were to live forever." - Gandhi

2

• Crazy people are not crazy if one accepts their
  reasoning
• Gabriel Garcia Marquez in
• Of Love and other demons

3
(No Transcript)
4
(No Transcript)
5
Apoptosis Implications

• Developing Embryo and to prevent malformations
• Deletion of activated mature T cells at the end
  of immune response
• Killing of target cells such as virus-infected
  cells or cancer cells by cytotoxic T cells and by
  natural killer cells
• Killing of inflammatory cells at the
  immuneprivileged sites such as the eye
• Unscheduled apoptosis in neurons causes ALS
  (Lou Gherig) Disease, Parkinsons disease
• DNA damaged cells if not repaired have to be
  killed if not - mutations and cancer.

6
Subacute and chronic cell injury Cellular
Accumulations
Endogenous
Exogenous
Fat
Carbon (Anthracotic)
Protein
Glycogen
Tattoo
Pigments Other
Lipofuscin
Melanin
Hemosiderin Uric Acid
Bacteria/virus
7
(No Transcript)
8
(No Transcript)
9
(No Transcript)
10
PEROXISOMAL ?-OXIDATION
MITOCHONDRIAL ?-OXIDATION
FATTY ACIDS
MICROSOMAL ?-OXIDATION
DICARBOXYLIC ACIDS
11
E
x
p
o
r
t
I
n
c
r
e
a
s
e
d

f
a
t

s
t
o
r
a
g
e
D
i
c
a
b
o
x
y
l
i
c
A
c
i
d
s
-
o
x
i
d
a
t
i
o
n
P
e
r
o
x
i
s
o
m
a
l


P
P
A
R
g
b
-
o
x
i
d
a
t
i
o
n
S
T
E
A
T
O
H
E
P
A
T
I
T
I
S
A
D
I
P
O
G
E
N
E
S
I
S

A
D
I
P
O
S
I
T
Y
12
FASTING ADIPOSE TISSUE/LIPOLYSIS
FATTY ACID INFLUX
PPAR? MEDIATED INDUCTION OF
FATTY ACID OXIDATION SYSTEMS
---
PPAR?-/- PPAR?-/- AOX-/-
WILD TYPE
PPAR?-/- PPAR?-/- AOX-/-
WILD TYPE
13
Fatty Liver Steatosis and steatohepatitis
Alcoholic Steatosis/ Steatohepatitis ASH
Non-Alcoholic Steatosis/ Steatohepatitis NASH
Alcoholism Fatty Liver Mallory Bodies Acute
Hepatitis Lipogranulomas
Obesity Excess Energy Diabetes
Mellitus Syndrome X Metabolic
Disturbances Fatty acid oxidation
Obesity (central) Type 2 Diabetes Mellitus
Insulin Resistance Dyslipidemia
HypertensionCardiovascular Disease later
14
Excess Energy
Increased Fatty Acid Uptake
Increased Triglyceride synthesis
Increased Fatty Acid Synthesis
Decreased Apoprotein Synthesis
Decreased Lipoprotein Secretion
Decreased Fatty Acid Oxidation
15
(No Transcript)
16
(No Transcript)
17
(No Transcript)
18
(No Transcript)
19
(No Transcript)
20
(No Transcript)
21
(No Transcript)
22
(No Transcript)
23
(No Transcript)
24
Protein and Proteinaceous Products
Intermediary filaments
Alcoholism
Hepatocyte
Mallory Body
?1-AT Deficiency
?1-AT accumulation
Hepatocyte
Glu 342 Lys
Alzheimers
Neurons
Neurofibrillary tangles
Neurofibrils?-amyloid
Parkinsons Disease
Neurons
Lewy Body
Neurofibrils
Huntington Disease
Nuclear Inclusions
Polyglutamine CAG gt 38
mild- slow-late onset gt70
aggressive, rapid, early onset
Neurons
25
I
Ubiquitin
Protein
Polyubiquitination
II
Ubiquitin
III
Proteosome
Peptides
26
Ubiquitin-Proteasome

• Most proteins are degraded via the non-lysosomal
  ubiquitin-proteasome pathway.
• Target proteins are covalently linked at
  lysine-residues to multiple ubiquitin molecules
  (polyubiquitination)
• Ubiquitinated protein is the substrate for 26S
  proteasome for degradation. ATP dependent process
• Formation of residues 3-20 amino acid for reuse
• Degrades transcription factors and many other
  regulatory molecules and more stable proteins
• Ubiquitin is a 76 amino acid protein
• Inability to degrade ubiquitinated proteins leads
  to accumulation of junk in the cells.

27
(No Transcript)
28
(No Transcript)
29
(No Transcript)
30
(No Transcript)
31
THE BEST PROPHET OF THE FUTURE IS THE PAST



FORTUNE COOKIE
FORGET THE PAST OR THE PAST WILL KILL YOU


V.
S. NAIPAUL
THE LIFE YOU WILL LIVE IS THE LIFE YOU HAVE
LIVED
V. S. NAIPAUL IN

THE GUERILLAS
EVEN GOD CANT CHANGE THE PAST, ARISTOTLE SAID,
BUT WITH ENOUGH SKILL AND COURAGE, WE CAN
LOOK BACK ON IT AND MOURN, AND REJOICE AND
UNDERSTAND, AND FORGE AHEAD
32
Lipofuscin

• Wear tear aging pigment
• Undigested material accumulating in endstage
  lysosomes residual bodies
• Yellow-brown granules autofluorescent
• Lipid peroxidation and chronic oxidative stress
  due to ROS
• More in non-dividing (myocardium) and
  conditionally dividing (liver) cells
• Cells can discharge this material when cells die
  or divide

33
(No Transcript)
34
(No Transcript)
35
(No Transcript)
36
(No Transcript)
37
(No Transcript)
38
Melanin

• Melanocyte L-TYROSINE
• Tyrosinase
• Dihydroxyphenylalanine (DOPA)
• Oxidation
• DOPA
  Quinone Dopachrome
  Dihydroxyindole indole quinone
• Polymerization to Melanin (insoluble)
• Melanin Increase Sunlight Addison Disease
  Hemachromatosis
• Melanin Decrease
• Albinism Melanocytes present but no tyrosinase.
• Leukoderma (Vitiligo)- Melanocytes absent
  destruction of melanocytes- patchy expansive-
  immunologic injury?

39
(No Transcript)
40
(No Transcript)
41
Melanin

• Melanocyte L-TYROSINE
• Tyrosinase
• Dihydroxyphenylalanine (DOPA)
• Oxidation
• DOPA
  Quinone Dopachrome
  Dihydroxyindole indole quinone
• Polymerization to Melanin (insoluble)
• Albinism Melanocytes present but no tyrosinase.

42
Melanin

• Melanocyte L-TYROSINE
• Tyrosinase
• Dihydroxyphenylalanine (DOPA)
• Oxidation
• DOPA
  Quinone Dopachrome
  Dihydroxyindole indole quinone
• Polymerization to Melanin (insoluble)
• Leukoderma (Vitiligo)- Melanocytes absent
  destruction of melanocytes- patchy expansive-
  immunologic injury?

43
STORAGE IRON
Reticuloendothelial System Liver, bone marrow,
spleen
HEMOSIDERIN
HEMOCHROMATOSIS
HEMOSIDEROSIS
CYSTEINE 282 TYROSINE
NUTMEG LIVER
HEART FAILURE CELLS
OVULATION CORPUS LUTEUM
ENDOMETRIOSIS (CHOCOLATE CYST)
BRUISE
44
BLACK EYE
HEMATOMA EXTRAVASATION OF BLOOD
RED-BLUE- BLACK DEOXYGENATED BLOOD
MACROPHAGES RBC INGESTION GREEN BILE
(BILIVERDIN) RED BILE (BILIRUBIN)
GOLDEN-YELLOW IRON AS FERRITIN-HEMOSIDERIN
45
(No Transcript)
46
(No Transcript)
47
(No Transcript)
48
(No Transcript)
49
(No Transcript)
50
(No Transcript)
51
RNA DNA
ADENINE GUANINE
HYPOXANTHINE
XANTHINE
XOX

XOX
XOX
URIC ACID

URATE OXIDASE
ALLANTOIN
52
Mycobacterium Avium Intracellulare- in AIDS
53
Mycobacterium Avium Intracellulare- in AIDS (HIV)
Acid Fast Stain
54
Xanthomas
55
Carbon Pigment-
56
(No Transcript)
57
Coal-miners Lung
58
(No Transcript)
59
(No Transcript)
60
DYSTROPHIC NORMAL SERUM CALCIUM DEAD
DYING TISSUES (TOMBING)
ATHEROSCLEROSIS
CALCIFIED GRANULOMAS
LITHOPEDIAN
CALCIFIC AORTIC STENOSIS
BICUSPID AORTIC STENOSIS
EXTRASKELETAL CALCIFICATION
MULTIPLE MYELOMA HYPERPARATHYROIDISM BONE
METASTASIS END-STAGE KIDNEY SARCOIDOSIS
HYPERVITAMINOSIS D
METASTATIC HYPERCALCEMIC STATES CALCIFICATION IN
NORMAL TISSUES LUNG, KIDNEY, GASTRIC MUCOSA
61
(No Transcript)
62
(No Transcript)
63
(No Transcript)
64
(No Transcript)
65
(No Transcript)
66
(No Transcript)
67
(No Transcript)
68
(No Transcript)
69
(No Transcript)
70
(No Transcript)