Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.
-
Upload
kelly-stevenson -
Category
Documents
-
view
215 -
download
0
Transcript of Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.
![Page 1: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/1.jpg)
Cellular apoptosis and disease
Zhao Mingyao
BMC.ZZU
![Page 2: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/2.jpg)
![Page 3: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/3.jpg)
Background knowlege
![Page 4: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/4.jpg)
Concept of apoptosis
autonomic and ordered cell death controlled by gene or called as programmed cell death (PCD)
![Page 5: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/5.jpg)
nematode
drosophila mouse
research model
![Page 6: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/6.jpg)
• Nematode : total 1090 cells in young, 959 cells in adult, 131 cells lost ?
• Time : 1 h r • Gene : 14 gene known
Classical Apoptosis model
![Page 7: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/7.jpg)
1.Differences between necrosis and apoptosis
![Page 8: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/8.jpg)
Apoptotic bodies溶酶释出,
炎症反应
ATPATP(-)
Passive
Active new protein
Strong stimulation
Weak ~
?
Comparison between apoptosis & necrosis
![Page 9: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/9.jpg)
2.The biological meanings of apoptosis
![Page 10: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/10.jpg)
By the time I was born, more of me had died than survived. It was no wonder I cannot remember; during that time I went through brain after brain for nine months, finally contriving the one model that could be human, equipped for language.
In humans, as many as 1011 cells die in each adult each day and are replaced by other cells. The mass of cells we lose each year is close to our entire body weight!
![Page 11: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/11.jpg)
①Maintain normal development and growth:remove excess cell
② Maintain homeostasis : remove damaged, mutant , senile cell
③Active defense function: block replication of cells infected by virus
Apoptosis importance
![Page 12: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/12.jpg)
3. apoptosis process (period)
![Page 13: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/13.jpg)
Course of cellular apoptosis
1.Transduction of apoptosis signal
starting signal Ca2+ 、 cAMP 、 ceramide
2. Activation of apoptosis gene
express enzymes and other substance
3. Execution of cellular apoptosis
DNase and Caspases
4. Removal of apoptotic cell engulfed by near cell ( Mφor other cell )
![Page 14: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/14.jpg)
TSP
TSP: thrombospondin
![Page 15: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/15.jpg)
4.The two major biochemical changes in the courses of apoptosis
![Page 16: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/16.jpg)
(1)Endogenous Dnase activation and its effect
• A series cellular ST activation
• Execution of chromosome DNA cleavage
![Page 17: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/17.jpg)
Fragment of DNA : classic ladder pattern ?
300 kb pieces
50kb
180~200bp or its
whole folds fragment
5min
90min
Endonucleases first cleave
chromosome caspase-activated deoxyribonucleaus
poly (ADP-ribose)polymerase
![Page 18: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/18.jpg)
–
+necrosis apoptosis
famous nucleosomal ladder
DNA electrophoresis
![Page 19: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/19.jpg)
(2) Caspases activation and its effect
A group of protease ( 13 members )cysteine-containing aspartate-spicific protease
caspases
note:Cysteine 半胱 aa Aspartate 天冬 aa
![Page 20: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/20.jpg)
Structure and classification of procapases
![Page 21: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/21.jpg)
Caspases function
① Deactivating inhibitor of apoptosis: as Bcl-2
② Hydrolyzing proteoin structure, cellular decomposing, apoptotic body
③ Hydrolyzing the related active proteins : make them to gain or lose function
![Page 22: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/22.jpg)
Apoptosis signal pathway
![Page 23: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/23.jpg)
1. Death receptor pathway
![Page 24: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/24.jpg)
Inducing factor →ΔΨm↓
PTP
permeability↑→apoptosis starting factor ( Cyt. C , Apaf , AIF ) released
Abbreviation note:
•PTP----permeability transition pore
•Apaf----apoptosis protease activated factor
•Cyt.C----cytochrome C
•AIF---- apoptosis inducement factor
2. Mitochondrial pathway
![Page 25: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/25.jpg)
3. 3. Endoplasmic reticulumial pathway
![Page 26: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/26.jpg)
![Page 27: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/27.jpg)
Regulators of apoptosis
![Page 28: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/28.jpg)
1. Bcl-2 family pro in apoptosis
• Bcl-2, Bcl-XL, Mcl-1 promote survival
(anti-apoptotic pro)
• Bax, Bad, Bak, Bid induce death
(pro-apoptotic pro)
cell
![Page 29: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/29.jpg)
bcl-2 function
• Binding Apaf-1
• Prevent release of Cyto C
• Regulator of Ca2+ homeostasis
• Antioxidant
![Page 30: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/30.jpg)
2. IAP in apoptosis
• (IAP)/BIRP gene family: XIAP, c-IAP-1, c-IAP-2, ILP-2, NAIP, Livin and Apollon
• Block apoptosis
inhibit initiator and effector caspases
( proteolytic processing and enzymatic activity)
BIRC # for "baculoviral IAP repeat-containing".
IAP: inhibitor of apoptosis protein
![Page 31: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/31.jpg)
The "Inhibitor of Apoptosis Proteins" family
Characterization of IAP family members
• BIRC1 (Neuronal apoptosis inhibitory protein; NAIP)
• BIRC2 (API1; HIAP2; cIAP1; MIHB)
• BIRC3 (API2; HIAP1; cIAP2; MIHC)
• BIRC4 (XIAP; API3; MIHA; ILP)
• BIRC5 (Survivin; API4; TLAP)
• BIRC6 (Apollon; BRUCE)
• BIRC7 (MLIAP; KIAP; Livin)
• BIRC8: (ILP-2; TIAP)
![Page 32: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/32.jpg)
3. Apoptosis Inhibitory factor cytokine— IL-2 , NGF
hormone— ACTH 、 testosterone , estrogen other— Zn2+(zinc), phenobarbital , Cysteine
protease inhibitor, EB virus, neutroamino acid
![Page 33: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/33.jpg)
4. Inducers of apoptosis
Apoptosis induced by death signal:
hormone, GF↑↑, GC
physic and chemic factor
immune
microbe
TNFa, Fas
Adaptor (FADD,TRADD)
Caspase 8
![Page 34: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/34.jpg)
NGF NGF+Ceramide 24h
PC12 cell
Condensed and fragmented nuclei of dead cells
![Page 35: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/35.jpg)
5. Oxidative stress induce apoptosis
• P53 gene activation
• activating Ca2+/Mg2+ -dependent Dnase
• Ca2+ influx↑
• activating NF-κB and Ap-1 ( Fas)
![Page 36: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/36.jpg)
G1
S
G2
M
Cyclin A+CDK
Cyclin A+CDK1
Cyclin B
Cyclin D
p53
Bax+ Bcl-2↓
molecular policeman?
Blocking IGF+R
6. P53 in apoptosis
![Page 37: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/37.jpg)
7. [Ca2+] dyshomeostasis
• activating Ca2+/Mg 2+ -dependent Dnase
• activating nuclear transcription factor related to apoptosis
• Ca 2+ promoting to exposing enzymolytic sites between nuclear nuleosomes
![Page 38: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/38.jpg)
Some diseases related to apoptosis
![Page 39: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/39.jpg)
1. Tumor and apoptosis
insufficiency of apoptosis• Bcl-2 express↑• P53 mutation or loss
![Page 40: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/40.jpg)
2. Immune diseases and apoptosis
(1) Autoimmune diseases
• Hashimoto’s thyroiditis (HT, chronic lymphocytic thyroiditis ) : Fas/FasL mediated apoptosis
• SLE (Systemic lupus erythematosus)
![Page 41: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/41.jpg)
•SLE (Systemic
• lupus erythematosus)
![Page 42: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/42.jpg)
(2)AIDS
HIV CD4+ cell damaged selectively
![Page 43: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/43.jpg)
3. Heart failure and apoptosisapoptosis
myocyte hypertrophy and widening of interstitial spaces due to deposition of collagen, inflammatory cells and amyloid.
![Page 44: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/44.jpg)
4. Atherosclerosis and in apoptosis
Insufficiency and excess of apoptosis exist together
oxLDL ↑
activated plt ↑
Ag II
hypertension
Endothelia barrier↓
Endothelia ~↑
Smooth ~ insufficiency
(proliferation↑>apoptosis↑ )
![Page 45: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/45.jpg)
Neuron retrogression—— loss of neuron in
hippocampus and basal nuclei
• Loss of Cholinergic neurons reachs 30%~50% , involved cortex
5. Alzheimer disease and apoptosis
![Page 46: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/46.jpg)
![Page 47: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/47.jpg)
AD mechanism
disease cause such as OFR
Ca2+ inward flowing↑
activating related genes
neuron
promoting β- amyloid content ↑
Tan pro overphosphorylation
![Page 48: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/48.jpg)
Regulating apoptosis in treating diseases
![Page 49: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/49.jpg)
Regulating apoptosis in treating diseases
• Interfere or promote apoptosis
• Molecular targets
![Page 50: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/50.jpg)
bociwana
Jibuti
erlitiya
ZZU in China
Class, day, year
![Page 51: Cellular apoptosis and disease Zhao Mingyao BMC.ZZU.](https://reader036.fdocuments.us/reader036/viewer/2022062517/56649f355503460f94c52c3c/html5/thumbnails/51.jpg)
Thanks!