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Apoptosis-related Diseases Insufficient apoptosis Excessive apoptosis Coexistence of insufficient and excessive apoptosis Balance of Growth and Apoptosis Growth Apoptosis Apoptosis and Diseases Diseases Heart failure AIDS AD, PD Cancer Autoimmune diseases Atherosclerosis Mechanism Apoptosis Ischemia, inflammation, etc. HIV infection of T4 cell Ischemia, inflammation, etc P53, Bcl-2 Autoreactive T cells or B cells Endothelial cell, muscle cell Apoptosis Genes mutated in Diseases Gene Tumor necrosis factor receptor 1 (TNF-R1) Fas (CD95; Apo-1) Fas ligand Perforin Caspase 10 bcl-10 p53 Bax bcl-2 c-IAP2 NAIP1 Affected disease Familial periodic fever syndrome Autoimmune lymphoproliferative syndrome type I(ALPS I), malignant lymphoma, bladder cancer Systemic lupus erythematodes Familial hemophagocytic lymphohistiocytosis (FHL) Autoimmune lymphoproliferative syndrome type II (ALPS II) Non-Hodgkin’s lymphoma Various malignant neoplasms Colon cancer; hematopoetic malignancies Non-Hodgkin’s lymphoma Low-grade MALT lymphoma Spinal muscular atrophy Insufficient Apoptosis in Diseases Autoimmune disease, Tumor, virus infection, etc Proliferation Apoptosis (1) Tumor Pathogenesis for tumor: stimulated cell proliferation inhibited cell apoptosis Cell survival > cell death in diseased tissue Cell apoptosis is actually one of the natural anticarcinogenic mechanisms Signaling Pathways Involved in Apoptosis (Molecules highlighted in red have been found mutated in tumor cells) Tumor----P53 mutation Chemicals Virus Radiation (2) Autoimmune diseases The lesion is caused by attack of auto-antibody or sensitized T cell to self-antigen. Normally, T cells against auto-antigen are eliminated by apoptosis during the development. When the negative selection is deregulated (thymus diseases), T cells survive and abnormally proliferate, then attack self tissue, lead to autoimmune diseases. Mechanism of autoimmune diseases — Disrupted apoptosis of self-reactive cell Insertion mutation of Fas Decreased expression of Fas protein Point mutation of FasL Structural abnormity of FasL Escape the negative selection of self-reactive T cells Autoimmune diseases Rheumatoid arthritis It is caused by decreased apoptosis and increased proliferation of arthral cell ; Increased IL-1 and TGF-β1 and decreased Fas expression, which inhibit apoptosis; Increased Bcl-2、Bcl-XL, which increased the threshold of apoptosis; Resistance of T-cells to apoptosis. Excessive Apoptosis in Diseases AIDS, neurodegenerative diseases, aberrant myocardial ischemicreperfusion (1) Acquired Immune Deficiency Syndrome —AIDS HIV infection increased Fas gene expression gp120glycoprotein expression + receptor in CD4 lymphocyte infusion of infected CD4 cell leads to syncytin formation produce tat protein (enhance Fas expression) secret TNF CD+4T- lymphocyte apoptosis AIDS (2) Cardiovascular diseases Cell death induced by ischemia-reperfusion Apoptosis Early stage Peripheral region of infarct Mild ischemia Chronic Necrosis Later stage Center of infarct Severe ischemia Acute Possible mechanism (myocardial cell apoptosis induced by ischemia-reperfusion): (1) (2) (3) (4) oxidative stress; calcium overload; p53 gene activation; death receptor Fas, TNF over expressed. Heart failure: Myocardial cell diminishes in pressureoverload-induced heart failure Possible mechanisms: Oxidative stress; cytokines; ischemia; hypoxia; pressure or volume overload, neural-endocrine system deregulation; Lead to myocardial cell apoptosis (3) Neurodegenerative diseases Alzheimer disease,Parkinson disease, Huntington disease, multiple sclerosis Factors involved in neuronal apoptosis: b-amyloid peptide, calcium overload, oxidative stress, neuronal growth factor insufficiency, etc. Lead to neuronal cell apoptosis Coexistence of Excessive and Insufficient Apoptosis in Diseases oxidative LDL platelet activation AngⅡ hypertension excess apoptosis in endothelium insufficiency in smooth muscle atherosclerosis Prevention and Therapeutic Potential of Apoptosis •Interfere signal transduction, signal molecules, receptors, 2nd messengers, etc •Regulate apoptosis-related enzymes and genes •Prevent decrease in mitochondria trans-membrane potential •Others