This document provides an overview of apoptosis in health and disease. It begins with definitions of apoptosis and its key characteristics. It then discusses the intrinsic and extrinsic pathways of apoptosis, involving proteins like caspases, Bcl-2 family members, cytochrome c, and death receptors. The document outlines the morphological changes seen in apoptotic cells and methods to detect apoptosis. It discusses the significance of apoptosis in physiological conditions like development and tissue homeostasis. Finally, it examines how dysregulation of apoptosis can lead to diseases like cancer, autoimmune disorders, and neurodegenerative conditions.
Apoptosis is a
-pathway of cell death that is
-induced by an internally regulated program
-in which cells destined to die activate intrinsic enzymes that --degrade the cells’ own nuclear DNA and also nuclear and cytoplasmic proteins
-With minimal host reaction.
Content-
1. Background
2. Introduction
3. Difference between apoptosis and necrosis
4. Apoptosis in biologic processes
5. Apoptosis in pathologic processes
6. Morphologic features
7. Techniques to identify and count apoptotic cells
8. Biochemical changes
9. Molecular mechanism of apoptosis
10. Recent advancement and emerging trends in apoptosis
11. References
Apoptosis is a
-pathway of cell death that is
-induced by an internally regulated program
-in which cells destined to die activate intrinsic enzymes that --degrade the cells’ own nuclear DNA and also nuclear and cytoplasmic proteins
-With minimal host reaction.
Content-
1. Background
2. Introduction
3. Difference between apoptosis and necrosis
4. Apoptosis in biologic processes
5. Apoptosis in pathologic processes
6. Morphologic features
7. Techniques to identify and count apoptotic cells
8. Biochemical changes
9. Molecular mechanism of apoptosis
10. Recent advancement and emerging trends in apoptosis
11. References
Apoptosis is a process of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death.
this is a series of notes on general pathology, useful for undergraduate and post graduate pathology students. Notes have been prepared from standard textbooks and are in a format easy to reproduce in exams.
Apoptosis also known as cell suicide. Difference between necrosis and apoptosis. Changes in apoptosis. Mechanism of apoptosis. Functional significance of apoptosis. Applied aspects of apoptosis
Apoptosis is a process of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death.
this is a series of notes on general pathology, useful for undergraduate and post graduate pathology students. Notes have been prepared from standard textbooks and are in a format easy to reproduce in exams.
Apoptosis also known as cell suicide. Difference between necrosis and apoptosis. Changes in apoptosis. Mechanism of apoptosis. Functional significance of apoptosis. Applied aspects of apoptosis
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Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
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2 Case Reports of Gastric Ultrasound
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
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Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
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These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
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Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
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5th edition of the Diagnostic and Statistical Manual of Mental Disorders
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In the DSM-5, all types of substance abuse and dependence have been
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AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
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of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
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June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
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- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
3. Apoptosis - Definition
• A pathway of cell death induced by a tightly
regulated suicidal program, in which the
cells destined to die activate enzymes that
degrade cells own nuclear DNA and nuclear,
cytoplasmic proteins.
sclero dinesh
4. Kerr Wyllie and Currie paper, British Journal of Cancer, 1972 Aug;26(4):239-57
"We are most grateful to Professor James
Cormack of the Department of Greek,
University of Aberdeen, for suggesting this
term. The word "apoptosis" (ἁπόπτωσισ) is
used in Greek to describe the "dropping off"
or "falling off" of petals from flowers, or
leaves from trees”.
mev
7. • John Foxton Ross Kerr – Distinguish
apoptosis from traumatic cell death (1962).
mev
8. Nobel prize in 2002 – Sydney Brenner , Horvitz, John
Buston.
‘identified gene that control apoptosis’
Study done in “Caenorhabditis Elegans”
9. Significance of apoptosis
• During development many cells are produced in excess which
eventually undergo programmed cell death and thereby contribute to
sculpturing many organs and tissues [Meier, 2000]
• In human body about one lakh cells are produced every second by
mitosis and a similar number die by apoptosis (Vaux and Korsmayer
,1999, cell)
• Between 50 and 70 billion cells die each day due to apoptosis in the
average human adult. For an average child between the ages of 8 and
14, approximately 20 billion to 30 billion cells die a day. ( Karam, Jose A.
(2009). Apoptosis in Carcinogenesis and Chemotherapy. Netherlands: Springer.
ISBN 978-1-4020-9597-9)
• Without apoptosis, human gut can grow up to 12 miles in length
• Whole epithelial lining in our body changes every 23 days
10.
11. sclero dinesh
APOPTOSIS NECROSIS
NATURAL YES NO
EFFECTS BENEFICIAL DETRIMENTAL
Physiological or
pathological
Always pathological
Single cells Sheets of cells
Energy dependent Energy independent
Cell shrinkage Cell swelling
Membrane integrity
maintained
Membrane integrity lost
12. sclero dinesh
APOPTOSIS NECROSIS
Role for mitochondria and cytochrome C No role for mitochondria
No leak of lysosomal enzymes Leak of lysosomal enzymes
Characteristic nuclear changes Nuclei lost
Apoptotic bodies form Do not form
DNA cleavage No DNA cleavage
Activation of specific proteases No activation
Regulatable process Not regulated
Evolutionarily conserved Not conserved
Dead cells ingested by neighboring cells Dead cells ingested by neutrophils and
macrophages
13. WHY APOPTOSIS?
To eliminate cells that :
• are potentially harmful
• have outlived their usefulness / aged
• are damaged beyond repair
14. • Since it is genetically regulated , apoptosis is
sometimes referred to as programmed cell death.
• Certain forms of necrosis , called “ necroptosis”
are also genetically programmed, but by a distinct
cell of genes.
18. 1.Caspases:
• ‘c’ - cysteine protease(an enzyme with cysteine in its
active site)
‘aspase’- ability of these enzyme to cleave after aspartic
acid residues
• More than 10 members
• Central executioners of cell death
• Depending on order in which they are activated during
apoptosis, they are divided into
• Initiator caspase - 8, 9
• Executioner caspase -3, 6,7
Presence of cleaved,active caspases is a marker for cells
undergoing apoptosis
19. 2.Bcl-2 proteins:
Family of more than 20 members - categorised in 3 groups
[ based on proapoptotic and antiapoptotic properties ,
and presence of BCL-2 homology (BH) domains ]
1) Antiapoptotic - BCL 2, BCL XL
• present on outer mito.membrane, cytosol and ER
Functn : make outer mitochondrial membrane
impermeable and prevent leakage of cytochrome
c.
Stimulated by : growth factors , survival signals
BCL XL - BCL2 related protein, long isoform
20. 2) Proapoptotic – BAX , BAK
Funtn : promote outer mito. Membrane
permeability by forming a channel and
promote leakage of cytochrome c
3) Sensors – BAD , BIM , BID
• Act as sensors of cellular stress and
damage
• Regulate other two groups
BAX – BCL2 associated X protein,
BAK- BCL2 antagonist killer 1,
BAD- BCL2 antagonist of cell death,
BID – BH3 interacting domain death
agonist
21. 3. Cytochrome C
– Mitochondrial protein present at inter
mitochondrial space
– Can activate caspase cascade
4. Apaf-1 [ apoptosis activating factor – 1 ]
– Present in cytosol
– Forms apoptosome after combining with
cytochrome c
22. 5 . IAPS: [ inhibitors of apoptosis ]
– Newly discovered group of anti-apoptotic proteins
present in cytosol
– 7 members identified-NAIP,cIAP-1,cIAP-2 and survivin
– Bind to and inactivate caspases
– Survivin is involved in spindle cell formation
23. INTRINSIC PATHWAY [MITOCHONDRIAL PATHWAY]
Withdrawal of Radiation , Toxins, Free radicals
survival signals
DNA damage / misfolded proteins
Loss of antiapoptotic
(BCL2, BCLXL )
function ER STRESS
activation of sensors of Bcl 2 family
activation of proapoptotics- BAX, BAK
oligomerization and increase in outer
mitochondrial membrane permeability
Leakage of cytochrome c leakage of SMAC which bind into
cytosol to neutralise IAP’s in cytosol
24. Contd……
Cytochrome c in cytosol + APAF 1
Form Hexamer ( Apoptosome )
Binds to caspase- 9 (
critical initiator caspase)
Enzyme cleaves the adjacent caspase 9 molecules
i.e . Autoamplification process
Execution phase
26. Death Receptors
Members of TNF receptor family which contain a
cytoplasmic domain involved in protein-protein
interactions .i.e called Death Domain .
2 types of death receptors are there :
• TNFr (tumour necrosis factor receptor )
• FasR (fatty acid synthetase receptor )
The ligand for Fas is called FasL
The ligand for TNFr is TNFα
Adaptor Proteins
also contain death domain
a. FADD [ Fas associated death domain ]
b. TRADD [ TNF receptor associated death domain]
27. FAS ligand TNF
Death
domains
Adaptor proteins
Pro-caspase 8 (inactive)
Caspase 8 (active)
Pro-execution caspase
(inactive)
Execution caspase (active)
• Fas and the TNF receptor
are integral membrane
proteins with their receptor
domains exposed at the surface of
the cell
• Binding of the complementary
deathactivator (FasL and TNF resp
ectively) transmits a signal to the
cytoplasm
• FADD /TRADD attach to death receptors
• Binds an inactive form of caspase-8
• M/L procaspase 8 molecules are brought
• They cleave and generate active
caspase 8
28. • This pathway can be inhibited by a protein FLIP
which binds to pro –caspase 8 and cannot
cleave it
• Some viruses and normal cells produces FLIP
and use this inhibitor to protect themselves
from Fas mediated apoptosis
FLIP – FLICE inhibitory protein
29. • Extrinsic and intrinsic pathway involve
fundamentally different molecules for their
initiation, but their may be an
interconnection between them.
Eg : in hepatocytes and pancreatic β cells,
caspase 8 produced by Fas signaling cleaves
and activate sensors of bcl family i.e BID
which then stimulate mitochondrial
pathway
30. EXECUTION PHASE
• Final phase of apoptosis
• Mediated by proteolytic cascade
• After initiator caspases ( 2, 8, 9 and 10) are cleaved to
generate its active form, the enzymatic death program
is set in motion by rapid sequential activation of the
executioner caspases – 3,6
• Caspase -3 activates DNase which causes degradation
of chromosomal DNA within the nuclei and causes
chromatin condensation.
• Caspase -3 induces cytoskeletal reorganisation and
disintegration of cell into apoptotic bodies.
31. REMOVAL OF DEAD CELLS
Factors by which apoptotic cells attracts phagocytes
towards them :
• Apoptotic bodies- “bite size”-edible for phagocytes
• Phosphatidyl serine “flips” out from inner to outer
layer –recognized by macrophages receptors
• Some apoptotic bodies express thrombospondin
recognized by phagocytes
• They are coated by Ab and C1q
33. MORPHOLOGY OF CELLS IN APOPTOSIS
• Cell Shrinkage and dense cytoplasm
• Chromatin condensation to periphery and later
fragmentation.
• Plasma membrane is intact
• Formation of cytoplasmic blebs and apoptotic
bodies.
• Structurally altered so that the apoptotic cell
becomes “tasty” for phagocytosis
• Phagocytosis of apoptotic bodies by macrophages
• Dead cell is rapidly cleared before contents are
leaked out
• No inflammatory reaction
34. MORPHOLOGY OF APOPTOSIS
Progressive cell shrinkage
Chromatin condensation
Plasma membrane blebbing
Apoptotic bodies
Phagocytosis - no inflammation
36. Various methods available for
detection of apoptotic cells
1) Light microscopy
• In H&E the apoptotic cell appears as round or
oval mass of intensely eosinophilic cytoplasm
with fragments of dense nuclear chromatin
41. 3) Gel electrophoresis
DNA ladder pattern Single cell gel
electrophoresis comet assay
showing apoptotic cell
42. 4) TUNEL [ terminal deoxy transferase
mediated dUTP nick end labelling ]
• Identify DNA breaks in
apoptosis
Apoptotic cells detected by TUNEL and fluoresce green;
while necrotic cells are stained with red-fluorescent
propidium iodide
44. APOPTOSIS IN PHYSIOLOGIC
CONDITIONS
1) Programmed destruction of
cells during embryogenesis
including implantation,
organogenesis ,
developmental involution
and metamorphosis.
Eg : separation of webbed
fingers and toes in embryo
45. Apoptosis in bud
formation during
which many
interdigital cells
die. They are stained
black by a TUNEL
method
Incomplete differentiation
in two toes due to lack of
apoptosis
sclero dinesh
46. 2) Involution of hormone-dependent tissues upon
hormone withdrawal…
Eg :
• Endometrial cell breakdown during menstrual
cycle
• Ovarian follicular atresia in menopause
• Regression of the lactating breast after weaning
• Prostatic atrophy after castration
47. 3) Cell loss in proliferating cell
populations
Eg :
• Immature lymphocytes in bone
marrow and thymus that fail to
express useful antigen receptors
• B lymphocytes in germinal centers
• Epithelial cells in intestinal crypts
So as to maintain a constant number…
48. 4) Elimination of potentially harmful self-reactive
lymphocytes
5) Death of host cells that have served their useful
purpose
Eg :
- Neutrophils in an a/c inflammatory response
- Lymphocytes at the end of an immune response
In these situations , cells undergo apoptosis
because they are deprived of necessary survival
signals such as growth factors.
49. Apoptosis: Role in Disease
TOO MUCH: Tissue atrophy
TOO LITTLE: Hyperplasia
Neurodegeneration
Thin skin
etc
Cancer
Athersclerosis
etc
50. APOPTOSIS IN PATHOLOGIC
CONDITIONS
Pathological condition arise as a result of
dyregulation in apoptosis……………….
i.e defective apoptosis with increase cell survival
OR
Increased apoptosis with increased cell death
51. DYSREGULATED APOPTOSIS
DISORDERS WITH DEFECTIVE
APOPTOSIS AND INCREASE CELL
SURVIVAL
Eg :
• Mutations of p53 -------------
CANCERS
• AUTOIMMUNE DISEASES
DISORDERS WITH INCREASED
APOPTOSIS AND EXCESS CELL
DEATH
Eg :
• NEURODENEGERATIVE D/S
• Ischemic injury
• Death of virus infected cells. Eg
-AIDS
52. Apoptosis: Role in Disease
Aging
Aging --> both too much and too little apoptosis
(evidence for both)
Too much (accumulated oxidative damage?)
---> tissue degeneration
Too little (defective sensors, signals?
---> dysfunctional cells accumulate
hyperplasia (precancerous lesions)
sclero dinesh
53. PREGNANCY ASSOCIATED DISEASE AND APOPTOSIS
• During pregnancy trophoblast cells from placenta
invade the uterine environment inorder to remodel
the maternal blood vessels and help establishing and
maintain sucessful pregnancy.
• Strict control over the cell proliferation and
apoptosis is required to achieve this.
• In some cases the process can be compromised
and excessive apoptosis of trophoblast cells
failure of fully remodel the maternal environment
complication of pregnancy
Eg : preeclampsia of pregnancy
54. AUTOIMMUNE D/S AND APOPTOSIS
IN HEALTHY BODY
• T and B – lymphocytes are cells of immune system that
are responsible for destroying infected or damaged cell
in the body.
• They mature in thymus, but before they can enter the
blood stream they are tested to ensure that they are
effective against foreign antigen and are also not
reactive against normal healthy cells.
• Any ineffective or self reactive T-cells are removed
through induction of apoptosis.
55. AUTOIMMUNE D/S AND APOPTOSIS ….contd
IN DISEASE :
• Poor regulation of apoptosis in T- lymphocyte results
Autoimmune D/s of cytotoxic T lymphocytes.
Eg : Behcet’s D/S, Ankylosing Spondylitis, SLE
• Poor regulation of apoptosis in B –cell
Eg : SLE , Scleroderma , Multiple sclerosis
• RHEUMATOID ARTHRITIS : excessive proliferation of
synovial cells is thought to be due in part to the
resistence of these cells to apoptosis.
• AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME [ALPS]
: mutation in FAS gene
56. Neurodegenerative D/S and Apoptosis
IN HEALTHY BODY :
• During development of central and peripheral nervous
system, many neurons undergo apoptosis that coincides
with synaptogenesis.
• Signals that determine whether or not developing neurons
live or die may include competition for a limited supply of
target derived neurotrophic factors and activation of
receptors for excitatory neurotransmittor Glutamate.
• Initial overproduction of neurons followed by death of
some is an adaptive process that provide enough neurons
to form nerve cell circuits.
57. Neurodenerative D/S and Apoptosis…contd
Metabolic stress [ stroke, aging ]
Oxidative stress and free radicals DNA damage
Inherited mutations misfolded proteins
ER stress
APOPTOSIS increase Ca influx
58. Neurodenerative D/S and Apoptosis…contd
IN DISEASE :
• apoptosis of hippocampal neuron Alzheimer’s D/s
Over expression of Bcl 2
• apoptosis of midbrain neurons that uses NT’s
dopamine Parkinson’s Disease
• apoptosis of neurons in striatum which control body
movements Huntington’s Disease
• apoptosis of lower motor neurons Amyotrophic
Lateral Sclerosis
• In stroke activation of glutamate receptors which
act as a trigger to stimulate apoptosis
59. Apoptosis: Role in Disease
Cancer
• Apoptosis eliminates damaged cells (damage => mutations =>
cancer)
• Apoptosis is regulated by two major genes p53 & Bcl-2.
• Tumor suppressor p53 controls senescence and apoptosis
responses to damage.
• Mutations or overexpression of these genes will result in Cancer.
Most cancer cells are defective in apoptotic response (damaged,
mutant cells survive)
• High levels of anti-apoptotic proteins
or
Low levels of pro-apoptotic proteins ===> CANCER
60. Apoptosis: Role in Disease
Cancer
Virus associated cancer
•Several human papilloma viruses (HPV) have been implicated
in causing cervical cancer. One of them produces a protein (E6)
that binds and inactivates the apoptosis promoter p53.
•Epstein-Barr Virus (EBV), the cause of mononucleosis and
associated with some lymphomas
– produces a protein similar to Bcl-2
– produces another protein that causes the cell to increase its
own production of Bcl-2. Both these actions make the cell
more resistant to apoptosis (thus enabling a cancer cell to
continue to proliferate).
61. • Some B-cell leukemia and lymphomas express high
levels of Bcl-2, thus blocking apoptotic signals they may
receive.
• Melanoma (the most dangerous type of skin cancer)
cells avoid apoptosis by inhibiting the expression of the
gene encoding Apaf-1.
Apoptosis: Role in Disease
Cancer
62. •Other cancer cells express high levels of FasL, and can kill any
cytotoxic T cells (CTL) that try to kill them because CTL also
express Fas (but are protected from their own FasL).
•Some cancer cells, especially lung and colon cancer cells,
secrete elevated levels of a soluble "decoy" molecule that
binds to FasL, plugging it up so it cannot bind Fas. Thus,
cytotoxic T cells (CTL) cannot kill the cancer cells
Apoptosis: Role in Disease
Cancer
63. – Cancer cells
• Radiation and chemicals used in cancer therapy induce apoptosis
in some types of cancer cells.
sclero dinesh
Fig. 1: induced apoptosis in stomach carcinoma cells
Left: Before induction
Middle: 24h after induction
Right: 48h after induction
64. • Apoptosis and AIDS
Human Immunodeficiency Virus infects CD4+
T cells and HIV Tat protein increases the
expression of Fas receptor, resulting in
excessive apoptosis of T cells.
Hallmark- the decline in the number of the
patient's CD4+ T cells (normally about 1000
per microliter (µl) of blood).
sclero dinesh
65. ANTI-APOPTOTIC THERAPY IN DISEASES
• Stimulation of IAP - for the treatment of stroke,
spinalcord injuries , multiple sclerosis
• Synthetic nonspecific caspase inhibitors – trials going on
treatment of myocardial reperfusion injury, RA
• Aim of the treatment in neurodegenerative d/s is to
block apoptotic triggers and activation of anti -
apoptotic pathway ( by neurotrophic factors )
Eg : block amyloid β production t/t Alzheimer’s d/s
block glutamate receptor activation stroke
using neurotrophic factors like
vitamin E t/t alzheimer’s
Insulin like Growth factors t/t ALS
66. CONCLUSIONS
• Apoptosis is regarded as a carefully regulated energy dependent
process, characterized by specific morphological and biochemical
features in which caspase activation plays a central role.
• The importance of understanding the mechanistic machinery of
apoptosis is vital because programmed cell death is a component
of both health and disease, being initiated by various physiologic
and pathologic stimuli.
• Moreover, the widespread involvement of apoptosis in the
pathophysiology of disease lends itself to therapeutic
intervention at many different checkpoints.
• Understanding the mechanisms of apoptosis, and other variants
of programmed cell death, at the molecular level provides deeper
insight into various disease processes and may thus influence
therapeutic strategy.
67. References
• Robbins and Cotran,pathologic basis of disease, Kumar et al, 9th
edi.,2014
• Henry’s clinical diagnosis and management,21st edi,2007,546
• Review article on apoptosis, Indian Journal of Cancer ,vol 35, No.4,
sep- 2007 , 495-516
• Review article on various method available for detection of apoptotic
cell, Indian Journal of Cancer, july-sep 2013 , vol 50, issue 3.
• www.ncbi.nlm.nih.gov
• www.reading.ac.uk