1) The document discusses apoptosis and necrosis, two types of cell death. Apoptosis is programmed cell death where cells shrink and fragment in an orderly process. Necrosis is unprogrammed cell death caused by external injury or damage where cells swell and leak.
2) Apoptosis can be triggered internally through mitochondrial pathways or externally through death receptor pathways and leads to caspase activation and cell fragmentation. Cancer cells develop ways to avoid apoptosis like inhibiting proteins in these pathways.
3) Necrosis occurs when cells are damaged by external factors like toxins and involves cell and organelle swelling without fragmentation. Cancer cells and viruses can interfere with apoptosis to allow cancer progression.
1. Programmed cell death, also known as apoptosis, is essential for proper development and for destroying harmful cells.
2. Apoptosis is regulated by caspases, which are cysteine-dependent aspartate specific proteases. Caspases activate a proteolytic cascade that leads to cell death.
3. There are three main apoptotic pathways: the extrinsic pathway which involves death receptors, the intrinsic pathway which involves the mitochondria, and the granzyme pathway which uses granzymes from cytotoxic T cells and natural killer cells.
Three studies on programmed cell death in plants are summarized:
1. A study showed that heat-induced cell death in cucumber cotyledons resulted in DNA fragmentation and the release of cytochrome c from mitochondria into the cytosol, demonstrating conserved mechanisms with animal apoptosis.
2. A study found that caspase-specific peptide inhibitors effectively inhibited chemically-induced cell death in tomato cells, indicating caspase-like proteases mediate plant apoptotic pathways.
3. A study showed that anthocyanins from black soybeans protected human skin cells from UVB-induced reactive oxygen species, apoptosis, and caspase activation by preventing pro-apoptotic signaling.
The document summarizes programmed cell death or apoptosis. It describes apoptosis as a naturally occurring, genetically programmed process where a cell undergoes an organized breakdown. During apoptosis, cells shrink, break into membrane-bound fragments called apoptotic bodies, and are removed by phagocytes without causing inflammation. The document outlines the major pathways of apoptosis, including the intrinsic mitochondrial pathway and extrinsic death receptor pathway, and discusses the roles of caspase proteases and Bcl-2 family proteins in apoptosis signaling and regulation.
1) Apoptosis is a process of programmed cell death that is important for normal development and physiology, as it helps remove excess, damaged, or dangerous cells.
2) It occurs through intrinsic and extrinsic pathways that involve caspase proteases and results in characteristic cell changes like blebbing and nuclear fragmentation.
3) Between 50-70 billion cells die per day in humans due to apoptosis, which is critical for processes like immune system maturation and tissue remodeling.
The document provides an overview of apoptosis, or programmed cell death. It describes the three main pathways that can trigger apoptosis: the extrinsic or death receptor pathway, the intrinsic or mitochondrial pathway, and the perforin/granzyme pathway. The pathways activate initiator caspases that go on to activate executioner caspases, leading to characteristic cell changes like nuclear fragmentation and membrane blebbing. Apoptotic cells are then phagocytosed to prevent inflammation.
p53 has been described as “GUARDIAN ANGEL OF THE GENOME”
because it performs following mechanism:
DNA Repair
Cell growth arrest
Apoptosis (programmed cell death)
P53 is also known as cellular tumour antigen Ag, phosphoprotein
P53 or tumour suppressor p53.
P53 protein is encoded by TP53.
Tumor suppressor genes regulate cell growth and division. When functioning properly, they inhibit tumor formation but when mutated or inactivated, they lose this ability. Examples include p53, Rb, APC, BRCA1, BRCA2. p53 is mutated in 50% of cancers and regulates DNA repair/cell cycle arrest or apoptosis. Li-Fraumeni syndrome results from germline p53 mutations increasing cancer risk. The APC gene regulates beta-catenin to control cell growth. Mutations in tumor suppressor genes are often required for tumor development according to the two-hit hypothesis as seen with retinoblastoma caused by Rb mutations.
Apoptosis, or programmed cell death, is regulated by intrinsic and extrinsic pathways. The intrinsic pathway involves mitochondria releasing cytochrome c which activates caspase proteases, leading to DNA fragmentation and cell death. The extrinsic pathway involves death receptors activating caspase-8 through adaptor proteins. Caspases are cysteine proteases that cleave other proteins and dismantle the cell in apoptosis. The Bcl-2 family and inhibitor of apoptosis (IAP) proteins also regulate apoptosis. Dysregulation of apoptosis contributes to diseases like cancer and neurodegeneration.
1. Programmed cell death, also known as apoptosis, is essential for proper development and for destroying harmful cells.
2. Apoptosis is regulated by caspases, which are cysteine-dependent aspartate specific proteases. Caspases activate a proteolytic cascade that leads to cell death.
3. There are three main apoptotic pathways: the extrinsic pathway which involves death receptors, the intrinsic pathway which involves the mitochondria, and the granzyme pathway which uses granzymes from cytotoxic T cells and natural killer cells.
Three studies on programmed cell death in plants are summarized:
1. A study showed that heat-induced cell death in cucumber cotyledons resulted in DNA fragmentation and the release of cytochrome c from mitochondria into the cytosol, demonstrating conserved mechanisms with animal apoptosis.
2. A study found that caspase-specific peptide inhibitors effectively inhibited chemically-induced cell death in tomato cells, indicating caspase-like proteases mediate plant apoptotic pathways.
3. A study showed that anthocyanins from black soybeans protected human skin cells from UVB-induced reactive oxygen species, apoptosis, and caspase activation by preventing pro-apoptotic signaling.
The document summarizes programmed cell death or apoptosis. It describes apoptosis as a naturally occurring, genetically programmed process where a cell undergoes an organized breakdown. During apoptosis, cells shrink, break into membrane-bound fragments called apoptotic bodies, and are removed by phagocytes without causing inflammation. The document outlines the major pathways of apoptosis, including the intrinsic mitochondrial pathway and extrinsic death receptor pathway, and discusses the roles of caspase proteases and Bcl-2 family proteins in apoptosis signaling and regulation.
1) Apoptosis is a process of programmed cell death that is important for normal development and physiology, as it helps remove excess, damaged, or dangerous cells.
2) It occurs through intrinsic and extrinsic pathways that involve caspase proteases and results in characteristic cell changes like blebbing and nuclear fragmentation.
3) Between 50-70 billion cells die per day in humans due to apoptosis, which is critical for processes like immune system maturation and tissue remodeling.
The document provides an overview of apoptosis, or programmed cell death. It describes the three main pathways that can trigger apoptosis: the extrinsic or death receptor pathway, the intrinsic or mitochondrial pathway, and the perforin/granzyme pathway. The pathways activate initiator caspases that go on to activate executioner caspases, leading to characteristic cell changes like nuclear fragmentation and membrane blebbing. Apoptotic cells are then phagocytosed to prevent inflammation.
p53 has been described as “GUARDIAN ANGEL OF THE GENOME”
because it performs following mechanism:
DNA Repair
Cell growth arrest
Apoptosis (programmed cell death)
P53 is also known as cellular tumour antigen Ag, phosphoprotein
P53 or tumour suppressor p53.
P53 protein is encoded by TP53.
Tumor suppressor genes regulate cell growth and division. When functioning properly, they inhibit tumor formation but when mutated or inactivated, they lose this ability. Examples include p53, Rb, APC, BRCA1, BRCA2. p53 is mutated in 50% of cancers and regulates DNA repair/cell cycle arrest or apoptosis. Li-Fraumeni syndrome results from germline p53 mutations increasing cancer risk. The APC gene regulates beta-catenin to control cell growth. Mutations in tumor suppressor genes are often required for tumor development according to the two-hit hypothesis as seen with retinoblastoma caused by Rb mutations.
Apoptosis, or programmed cell death, is regulated by intrinsic and extrinsic pathways. The intrinsic pathway involves mitochondria releasing cytochrome c which activates caspase proteases, leading to DNA fragmentation and cell death. The extrinsic pathway involves death receptors activating caspase-8 through adaptor proteins. Caspases are cysteine proteases that cleave other proteins and dismantle the cell in apoptosis. The Bcl-2 family and inhibitor of apoptosis (IAP) proteins also regulate apoptosis. Dysregulation of apoptosis contributes to diseases like cancer and neurodegeneration.
Apoptosis, also known as programmed cell death, is a natural process by which cells self-destruct in response to internal or external signals. It is distinct from necrosis in that it involves chromatin condensation, cell shrinkage, and preservation of organelles, allowing for rapid engulfment by neighboring cells without inflammation. Apoptosis is initiated through either the intrinsic mitochondrial pathway or the extrinsic death receptor pathway and is executed by caspases, a family of cysteine proteases. It plays an essential role in development and homeostasis by removing damaged or unneeded cells.
Every cell has a natural life cycle involving birth and death. There are two main types of cell death: necrosis and apoptosis. Necrosis is accidental cell death due to external injury, while apoptosis is a carefully regulated process in which cells play an active role in their own death. During apoptosis, cells shrink, break into fragments, and are phagocytosed without causing inflammation. Precisely regulated apoptosis is important for normal development, immune function, and homeostasis, while defects can lead to diseases. Many cancer therapies aim to trigger the apoptosis pathway in tumor cells.
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
DNA can be damaged by physical, chemical, and environmental agents through various types of alterations including single or double base changes, breaks in the DNA chain, or cross-linkages between bases. The cell has multiple DNA repair mechanisms to correct damage including base excision repair, nucleotide excision repair, mismatch repair, and double-strand break repair. Base excision repair removes single damaged bases while nucleotide excision repair removes larger segments of damaged DNA. Mismatch repair corrects errors that occur during DNA replication. Double-strand break repair repairs more severe breaks in both strands of the DNA that can lead to chromosomal abnormalities. Defects in DNA repair pathways can result in increased cancer risks.
Telomere, Functions & Role in Aging & CancerZohaib HUSSAIN
Telomeres cap the ends of chromosomes and protect them from degradation during cell division. As cells divide, telomeres shorten due to the inability of DNA replication enzymes to fully copy chromosome ends. This limits a cell to around 50-70 divisions before entering senescence. Cancer cells activate telomerase to maintain telomere length, allowing unlimited division. Telomeres play a key role in both aging and cancer - their shortening limits the lifespan of normal cells but cancer cells overcome this via telomerase to achieve immortality and uncontrolled growth. Measuring and targeting telomerase may provide new strategies for cancer detection and treatment.
1. Apoptosis is a tightly regulated process of programmed cell death that involves the activation of caspases and degradation of nuclear and cellular components.
2. It can be triggered through intrinsic mitochondrial pathways or extrinsic death receptor pathways and plays an important physiological role in development, immune system maturation, and maintenance of tissue homeostasis.
3. Dysregulation of apoptosis can contribute to cancer, autoimmune diseases, and neurodegenerative disorders by allowing cells to survive inappropriately or undergo excessive cell death.
It describes about Structure and function of telomere, Telomerase enzyme, How does telomerase works?, Telomere replication, What happens to telomeres as we age?, Factors contribute to telomere shortening
Apoptosis, or programmed cell death, is an important physiological process that eliminates unwanted or damaged cells. There are two main pathways that trigger apoptosis - the extrinsic or death receptor pathway, and the intrinsic or mitochondrial pathway. The extrinsic pathway involves death receptors and ligands that activate caspase enzymes. The intrinsic pathway occurs in response to cellular stress and involves mitochondrial outer membrane permeabilization and the release of proteins like cytochrome c. This forms the apoptosome complex and activates caspase-9 and caspase-3, leading to apoptosis. Apoptosis is a highly regulated process involving Bcl-2 family proteins, caspase enzymes, and characteristic morphological changes including cell shrinkage, nuclear fragmentation, and membrane blebbing. Assays to detect
The document summarizes key aspects of apoptosis including:
- The origins and definition of the term apoptosis from Greek meaning "falling leaves".
- The significance of apoptosis in development and maintenance of tissues by removing excess or damaged cells.
- The morphological features of apoptosis including membrane blebbing, nuclear fragmentation, and formation of apoptotic bodies.
- The molecular mechanisms including caspase signaling pathways like the intrinsic pathway involving mitochondria and the extrinsic pathway involving death receptors.
- Regulatory mechanisms involving proteins like Bcl-2 that balance survival and death signals.
- Dysregulation of apoptosis can lead to diseases like cancer, autoimmune disorders, and HIV infection.
This presentation deals with basics of enzyme kinetics and introduction to various plots which aid in understanding the mechanism of inhibition of enzymes.
A detailed description of programmed cell death mechanism also called Apoptosis.
It explains about the factors, mechanism and pathways involved in the apoptosis.
The document discusses different types of cell death, including programmed cell death mechanisms like apoptosis and autophagy. It notes that cell death is tightly regulated and important for development, health, and eliminating damaged or infected cells. The major types of cell death covered are apoptosis (genetically programmed suicide), autophagy (housekeeping role), necrosis (unprogrammed trauma-induced death), and necroptosis (programmed necrosis).
This document discusses genetic mutations and DNA repair. It defines mutations as heritable changes in genetic material that can provide genetic variation and be the basis for evolution. Mutations can be caused spontaneously during DNA replication or cell division, or can be induced by environmental mutagens. The majority of mutations are neutral or harmful, with a small percentage being beneficial. Different types of mutations are described, including point mutations, insertions, deletions, and trinucleotide repeats. The effects of mutations on genes and proteins are explained. The timing of mutations as either germline or somatic is an important factor. Causes of spontaneous mutations like depurination and deamination are outlined.
Cyclin-dependent kinases (CDKs) are protein kinases that regulate critical cellular processes such as the cell cycle, transcription, and differentiation. CDKs are activated when bound to cyclin proteins and phosphorylate target proteins to regulate their activity. Different cyclin-CDK complexes are involved at different phases of the cell cycle, controlling checkpoints and ensuring DNA replication only occurs once per cycle. When DNA damage is detected, CDK inhibitors like p53 and p21 are activated, halting transcription and giving time for DNA repair.
1. Apoptosis is a tightly regulated process of programmed cell death that removes unwanted or damaged cells. It involves activation of caspases and degradation of nuclear DNA and proteins.
2. There are two main pathways that initiate apoptosis - the extrinsic pathway which involves death receptors, and the intrinsic pathway which involves the mitochondria. Both pathways activate caspases that execute the cell death program.
3. Disorders of apoptosis can result in disease states like cancer if cells fail to undergo apoptosis in response to damage, or neurodegeneration if excessive apoptosis occurs. A delicate balance of pro-apoptotic and anti-apoptotic proteins regulates apoptosis.
DNA methylation is a biological process where methyl groups are added to DNA, changing gene expression without altering the DNA sequence. It is essential for normal development in mammals and is associated with processes like genomic imprinting and carcinogenesis. DNA methyltransferases are enzymes that catalyze the addition of methyl groups to DNA from S-adenosyl methionine. DNA methylation plays important roles in gene silencing, X-chromosome inactivation, and suppressing viral genomes and repetitive elements incorporated into the host genome. Abnormal DNA methylation is also associated with cancer by transcriptionally silencing tumor suppressor genes.
Apoptosis, or programmed cell death, is an internally controlled suicide program where cells are removed with minimal disruption of surrounding tissue. It plays important roles in development, tissue homeostasis, and defense against infection and cancer. There are two main apoptotic pathways - the intrinsic mitochondrial pathway and the extrinsic death receptor pathway. Both pathways activate caspases, cysteine proteases that cleave proteins to execute the cell death program through processes like DNA fragmentation and formation of apoptotic bodies. Deregulation of apoptosis contributes to cancer development by allowing damaged or unnecessary cells to survive. Targeting the apoptotic pathway is a strategy for cancer treatment.
DNA methylation is an epigenetic mechanism that involves the addition of a methyl group to cytosine residues in DNA. It is catalyzed by DNA methyltransferase enzymes and plays a key role in gene expression and cellular differentiation. Aberrant DNA methylation, including both hypermethylation and hypomethylation, has been associated with cancer development by disrupting gene expression. Detection of DNA methylation patterns can provide insights into cancer biology and may have applications as a diagnostic tool.
Introduction
History
Tumor suppressor gene- pRB
- RB gene
- Role of RB in regulation of cell cycle
- Tumor associated with RB gene mutation
Tumor suppressor gene- p53
- What is p53 gene?
- Function of p53 gene
- How it regulates cell cycle
- What happen if p53 gene inactivated
- Cancer associated with p53 mutation
- Conclusion
- References
The document discusses the differences between apoptosis and necrosis. Apoptosis is a highly regulated and programmed process where cells undergo controlled death without inflammatory consequences. It occurs through mitochondrial changes, DNA fragmentation, cellular shrinkage, and formation of membrane-bound apoptotic bodies that are phagocytosed. In contrast, necrosis is unregulated cell death caused by external factors that results in cell swelling and rupture, releasing intracellular contents and triggering inflammation. The document outlines the multi-step process of apoptosis and provides examples of where it is important, such as in development and elimination of damaged cells.
This document summarizes several medical uses of propolis that have been demonstrated in clinical and pre-clinical studies. It discusses propolis' antimicrobial, antiviral, antioxidant, anticancer, cardiovascular, immune-modulating, and orodental properties. While some in vitro and animal research shows promising results, the document notes that high quality clinical evidence is still lacking for many potential applications of propolis.
Apoptosis, also known as programmed cell death, is a natural process by which cells self-destruct in response to internal or external signals. It is distinct from necrosis in that it involves chromatin condensation, cell shrinkage, and preservation of organelles, allowing for rapid engulfment by neighboring cells without inflammation. Apoptosis is initiated through either the intrinsic mitochondrial pathway or the extrinsic death receptor pathway and is executed by caspases, a family of cysteine proteases. It plays an essential role in development and homeostasis by removing damaged or unneeded cells.
Every cell has a natural life cycle involving birth and death. There are two main types of cell death: necrosis and apoptosis. Necrosis is accidental cell death due to external injury, while apoptosis is a carefully regulated process in which cells play an active role in their own death. During apoptosis, cells shrink, break into fragments, and are phagocytosed without causing inflammation. Precisely regulated apoptosis is important for normal development, immune function, and homeostasis, while defects can lead to diseases. Many cancer therapies aim to trigger the apoptosis pathway in tumor cells.
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
DNA can be damaged by physical, chemical, and environmental agents through various types of alterations including single or double base changes, breaks in the DNA chain, or cross-linkages between bases. The cell has multiple DNA repair mechanisms to correct damage including base excision repair, nucleotide excision repair, mismatch repair, and double-strand break repair. Base excision repair removes single damaged bases while nucleotide excision repair removes larger segments of damaged DNA. Mismatch repair corrects errors that occur during DNA replication. Double-strand break repair repairs more severe breaks in both strands of the DNA that can lead to chromosomal abnormalities. Defects in DNA repair pathways can result in increased cancer risks.
Telomere, Functions & Role in Aging & CancerZohaib HUSSAIN
Telomeres cap the ends of chromosomes and protect them from degradation during cell division. As cells divide, telomeres shorten due to the inability of DNA replication enzymes to fully copy chromosome ends. This limits a cell to around 50-70 divisions before entering senescence. Cancer cells activate telomerase to maintain telomere length, allowing unlimited division. Telomeres play a key role in both aging and cancer - their shortening limits the lifespan of normal cells but cancer cells overcome this via telomerase to achieve immortality and uncontrolled growth. Measuring and targeting telomerase may provide new strategies for cancer detection and treatment.
1. Apoptosis is a tightly regulated process of programmed cell death that involves the activation of caspases and degradation of nuclear and cellular components.
2. It can be triggered through intrinsic mitochondrial pathways or extrinsic death receptor pathways and plays an important physiological role in development, immune system maturation, and maintenance of tissue homeostasis.
3. Dysregulation of apoptosis can contribute to cancer, autoimmune diseases, and neurodegenerative disorders by allowing cells to survive inappropriately or undergo excessive cell death.
It describes about Structure and function of telomere, Telomerase enzyme, How does telomerase works?, Telomere replication, What happens to telomeres as we age?, Factors contribute to telomere shortening
Apoptosis, or programmed cell death, is an important physiological process that eliminates unwanted or damaged cells. There are two main pathways that trigger apoptosis - the extrinsic or death receptor pathway, and the intrinsic or mitochondrial pathway. The extrinsic pathway involves death receptors and ligands that activate caspase enzymes. The intrinsic pathway occurs in response to cellular stress and involves mitochondrial outer membrane permeabilization and the release of proteins like cytochrome c. This forms the apoptosome complex and activates caspase-9 and caspase-3, leading to apoptosis. Apoptosis is a highly regulated process involving Bcl-2 family proteins, caspase enzymes, and characteristic morphological changes including cell shrinkage, nuclear fragmentation, and membrane blebbing. Assays to detect
The document summarizes key aspects of apoptosis including:
- The origins and definition of the term apoptosis from Greek meaning "falling leaves".
- The significance of apoptosis in development and maintenance of tissues by removing excess or damaged cells.
- The morphological features of apoptosis including membrane blebbing, nuclear fragmentation, and formation of apoptotic bodies.
- The molecular mechanisms including caspase signaling pathways like the intrinsic pathway involving mitochondria and the extrinsic pathway involving death receptors.
- Regulatory mechanisms involving proteins like Bcl-2 that balance survival and death signals.
- Dysregulation of apoptosis can lead to diseases like cancer, autoimmune disorders, and HIV infection.
This presentation deals with basics of enzyme kinetics and introduction to various plots which aid in understanding the mechanism of inhibition of enzymes.
A detailed description of programmed cell death mechanism also called Apoptosis.
It explains about the factors, mechanism and pathways involved in the apoptosis.
The document discusses different types of cell death, including programmed cell death mechanisms like apoptosis and autophagy. It notes that cell death is tightly regulated and important for development, health, and eliminating damaged or infected cells. The major types of cell death covered are apoptosis (genetically programmed suicide), autophagy (housekeeping role), necrosis (unprogrammed trauma-induced death), and necroptosis (programmed necrosis).
This document discusses genetic mutations and DNA repair. It defines mutations as heritable changes in genetic material that can provide genetic variation and be the basis for evolution. Mutations can be caused spontaneously during DNA replication or cell division, or can be induced by environmental mutagens. The majority of mutations are neutral or harmful, with a small percentage being beneficial. Different types of mutations are described, including point mutations, insertions, deletions, and trinucleotide repeats. The effects of mutations on genes and proteins are explained. The timing of mutations as either germline or somatic is an important factor. Causes of spontaneous mutations like depurination and deamination are outlined.
Cyclin-dependent kinases (CDKs) are protein kinases that regulate critical cellular processes such as the cell cycle, transcription, and differentiation. CDKs are activated when bound to cyclin proteins and phosphorylate target proteins to regulate their activity. Different cyclin-CDK complexes are involved at different phases of the cell cycle, controlling checkpoints and ensuring DNA replication only occurs once per cycle. When DNA damage is detected, CDK inhibitors like p53 and p21 are activated, halting transcription and giving time for DNA repair.
1. Apoptosis is a tightly regulated process of programmed cell death that removes unwanted or damaged cells. It involves activation of caspases and degradation of nuclear DNA and proteins.
2. There are two main pathways that initiate apoptosis - the extrinsic pathway which involves death receptors, and the intrinsic pathway which involves the mitochondria. Both pathways activate caspases that execute the cell death program.
3. Disorders of apoptosis can result in disease states like cancer if cells fail to undergo apoptosis in response to damage, or neurodegeneration if excessive apoptosis occurs. A delicate balance of pro-apoptotic and anti-apoptotic proteins regulates apoptosis.
DNA methylation is a biological process where methyl groups are added to DNA, changing gene expression without altering the DNA sequence. It is essential for normal development in mammals and is associated with processes like genomic imprinting and carcinogenesis. DNA methyltransferases are enzymes that catalyze the addition of methyl groups to DNA from S-adenosyl methionine. DNA methylation plays important roles in gene silencing, X-chromosome inactivation, and suppressing viral genomes and repetitive elements incorporated into the host genome. Abnormal DNA methylation is also associated with cancer by transcriptionally silencing tumor suppressor genes.
Apoptosis, or programmed cell death, is an internally controlled suicide program where cells are removed with minimal disruption of surrounding tissue. It plays important roles in development, tissue homeostasis, and defense against infection and cancer. There are two main apoptotic pathways - the intrinsic mitochondrial pathway and the extrinsic death receptor pathway. Both pathways activate caspases, cysteine proteases that cleave proteins to execute the cell death program through processes like DNA fragmentation and formation of apoptotic bodies. Deregulation of apoptosis contributes to cancer development by allowing damaged or unnecessary cells to survive. Targeting the apoptotic pathway is a strategy for cancer treatment.
DNA methylation is an epigenetic mechanism that involves the addition of a methyl group to cytosine residues in DNA. It is catalyzed by DNA methyltransferase enzymes and plays a key role in gene expression and cellular differentiation. Aberrant DNA methylation, including both hypermethylation and hypomethylation, has been associated with cancer development by disrupting gene expression. Detection of DNA methylation patterns can provide insights into cancer biology and may have applications as a diagnostic tool.
Introduction
History
Tumor suppressor gene- pRB
- RB gene
- Role of RB in regulation of cell cycle
- Tumor associated with RB gene mutation
Tumor suppressor gene- p53
- What is p53 gene?
- Function of p53 gene
- How it regulates cell cycle
- What happen if p53 gene inactivated
- Cancer associated with p53 mutation
- Conclusion
- References
The document discusses the differences between apoptosis and necrosis. Apoptosis is a highly regulated and programmed process where cells undergo controlled death without inflammatory consequences. It occurs through mitochondrial changes, DNA fragmentation, cellular shrinkage, and formation of membrane-bound apoptotic bodies that are phagocytosed. In contrast, necrosis is unregulated cell death caused by external factors that results in cell swelling and rupture, releasing intracellular contents and triggering inflammation. The document outlines the multi-step process of apoptosis and provides examples of where it is important, such as in development and elimination of damaged cells.
This document summarizes several medical uses of propolis that have been demonstrated in clinical and pre-clinical studies. It discusses propolis' antimicrobial, antiviral, antioxidant, anticancer, cardiovascular, immune-modulating, and orodental properties. While some in vitro and animal research shows promising results, the document notes that high quality clinical evidence is still lacking for many potential applications of propolis.
Apoptosis is a tightly regulated form of programmed cell death that occurs through activation of intracellular enzymes. It plays an important role in physiological processes like embryogenesis and pathological conditions like viral infections. During apoptosis, cells shrink and their chromatin condenses. This leads to formation of apoptotic bodies that are phagocytosed by macrophages. The process is controlled through signaling pathways and mitochondrial permeability, which activate caspase enzymes that degrade DNA and proteins, cross-link proteins, and mark the cell for phagocytosis. Understanding apoptosis provides insights into development, disease mechanisms, and potential therapies.
Apoptosis is a tightly regulated process of programmed cell death where cells activate enzymes to degrade their own DNA and proteins. The plasma membrane remains intact but becomes a target for phagocytes. The dead cell and fragments are rapidly consumed before contents can leak out, preventing inflammation. Apoptosis eliminates damaged, unneeded, or harmful cells and occurs during development, tissue remodeling, and to limit damage from infections or DNA damage. It is characterized by cell shrinkage, chromatin condensation, and fragmentation into membrane-bound apoptotic bodies.
Initiation and maintainence of endometriosisKumgang Media
This document discusses the initiation and maintenance of endometriosis and adenomyosis. It covers Sampson's theory of retrograde menstruation as well as the metaplasia theory. Evidence is presented supporting and contradicting each theory. Predispositions like genetic, immunological, and endometrial changes are described. The roles of hormones, oxidative stress, environmental agents, epigenetics, inflammation, and iron are discussed in the maintenance of endometriosis. The effect on fertility and clinical implications are also summarized.
Apoptosis is a natural and programmed form of cell death that occurs in multicellular organisms. It was first described in 1842 and distinguished from necrosis in 1965. During apoptosis, a series of biochemical events lead to changes in the cell and its death, allowing it to be eliminated in a controlled way that does not cause inflammation. This process is regulated by complex signaling pathways within the cell and involves mitochondria, caspases and other components. Defects in apoptosis can result in cancer if cell death is inhibited or neurodegenerative diseases if cell death is excessive.
Apoptosis is a controlled, programmed cell death process that is essential for normal development and homeostasis. During apoptosis, cells actively trigger intracellular events that lead to cell fragmentation and phagocytosis without causing inflammation. Apoptosis is distinct from necrosis, which is unregulated cell death caused by external cellular injuries. Key aspects of apoptosis include activation of caspases, DNA fragmentation, and changes to cell membranes that mark cells for phagocytosis. Apoptosis pathways can be triggered by extracellular signals or internal cell damage and are important in development, tissue homeostasis, and diseases like cancer when the process goes awry.
This document discusses minerals and their functions in the human body. It covers major minerals like calcium, phosphorus, magnesium, and others. Calcium is the most abundant mineral and is essential for building bones and teeth, muscle contraction, nerve conduction, blood coagulation, and hormone secretion. Phosphorus also builds bones and teeth and is important for energy metabolism and acid-base balance. Magnesium is a co-factor for many enzymes and influences neuromuscular function and hormone secretion. Minerals are necessary for structure, function, and metabolism in the body.
This document reviews different types of hemopoietic growth factors called colony stimulating factors (CSFs), including their synthesis, effects on cells, and potential clinical applications and side effects. It discusses granulocyte-macrophage CSF (GM-CSF), granulocyte CSF (G-CSF), macrophage CSF (M-CSF), and multi-CSF, and their roles in stimulating various blood cell types. It also reviews early clinical trials using G-CSF and potential future directions using GM-CSF to treat cancers.
Apoptosis is a programmed cell death process that is essential for maintaining homeostasis. It involves the activation of caspases that trigger cell dismantling. Central regulators include Bcl-2 family proteins like Bax and Bak that induce mitochondrial membrane permeabilization and cytochrome c release upon activation. Cytochrome c then activates caspase-9 through formation of the apoptosome complex, triggering a caspase cascade that leads to apoptosis. Proteins like IAPs inhibit caspase activity and must be neutralized by other proteins like SMAC/Diablo to allow apoptosis to proceed. Together, these events ensure damaged or unnecessary cells are removed in a controlled manner.
Endometriosis is a disease where endometrial tissue grows outside the uterus, most commonly on the ovaries, fallopian tubes, and peritoneum. It typically affects women during their reproductive years and some of the main symptoms include painful periods, pain with intercourse, and infertility. Diagnosis involves a combination of clinical examination, imaging like ultrasound, and laparoscopy which remains the gold standard for direct visualization and biopsy of suspicious lesions. Common signs seen at laparoscopy include powder burn-like black or blue lesions on the pelvic organs and peritoneum.
Gene therapy involves inserting genetic material into cells to give them a new or restore a missing function. It can be used to treat cancer by modifying cancer cells at the molecular level, such as replacing a defective tumor suppressor gene like p53 to stop uncontrolled cell growth or induce cell death. Several approaches for gene therapy for cancer have shown promise in preclinical studies, including restoring tumor suppressor gene function, blocking oncogenes, and introducing "suicide genes" to selectively kill cancer cells. However, challenges remain to effectively target all cancer cells, including metastases.
Apoptosis, or programmed cell death, plays an important role in development, immunity, and maintenance of genomic integrity. Disruption of apoptosis can lead to diseases like cancer, autoimmune disorders, and neurodegenerative diseases. The document discusses the key stages and molecular mechanisms of apoptosis, including the roles of caspases, Bcl-2 family proteins, and death receptors. It also covers the importance of apoptosis in processes like immune system development, tissue remodeling, and response to DNA damage. Therapeutic strategies aim to either inhibit inappropriate apoptosis or induce apoptosis in conditions like cancer.
Necrosis is a type of cell death that occurs when cells are damaged by external factors like physical trauma, toxins, or ischemia. Key characteristics of necrosis include:
1) The cell undergoes physical and chemical changes and loses its normal structure/function as proteins denature and cell contents leak out.
2) Surrounding cells can become damaged when cellular contents from the necrotic cell are released, triggering an inflammatory response.
3) Morphologically, necrotic cells appear yellow, firm, and lose their normal nuclear structure. Specific patterns of necrosis include coagulative, caseation, and fat necrosis.
4) Necrosis is different from apoptosis, where cells undergo programmed, controlled
The document discusses necrosis and apoptosis. Necrosis is pathological cell death with complete destruction, and can be caused by infection, ischemia, hypoxia or chemicals/toxins. It involves loss of membrane integrity and cellular contents. Apoptosis is programmed cell death that can be physiological or pathological, involving cell shrinkage, nuclear condensation and fragmentation, and formation of apoptotic bodies that are phagocytosed. Key differences are that necrosis results in inflammation while apoptosis does not and involves phagocytosis.
Gene therapy aims to alter the phenotype of diseased cells by introducing exogenous nucleic acids like DNA. It involves choosing a cellular target, effector mechanism, delivery method, and effector gene. For cancer, common targets are tumor cells themselves or normal cells like stem cells. Effector mechanisms include gene replacement, suicide genes, and RNA-directed strategies. Delivery can be viral, non-viral, or involve artificial virus-like particles. Effector genes, promoters, and suicide genes must be chosen to match the intended target and effect. Some gene therapy strategies have shown effectiveness in clinical trials for cancers like breast and prostate.
This document summarizes various cytokine mediators and their functions. It discusses how cytokines are produced by different cell types and mediate effects through autocrine, paracrine and endocrine signaling. Specific cytokines discussed include interleukins (IL), interferons, tumor necrosis factor (TNF), and colony stimulating factors (CSFs). The roles of various cytokines in innate immunity, lymphocyte differentiation, and inflammation are described. Clinical uses of certain cytokines like IL-2, IL-11, anti-TNF antibodies, and GM-CSF are also mentioned.
The document discusses cell cycle, cell death, necrosis, and apoptosis. It defines necrosis as unprogrammed cell death caused by external factors like trauma or toxins. Necrosis leads to cell membrane rupture and inflammation. The types of necrosis include coagulative, liquefactive, fat, caseous, and gangrenous necrosis. Apoptosis is defined as programmed cell death that occurs normally in development and to remove damaged cells. During apoptosis, cells shrink and fragment into apoptotic bodies without membrane rupture or inflammation. The mechanisms of apoptosis involve intrinsic and extrinsic pathways that activate caspase enzymes to break down cellular components in a regulated execution phase.
La apoptosis es un proceso de muerte celular programada genéticamente que elimina células dañadas o no necesarias de forma controlada. Fue descubierta y denominada por John Kerr en la década de 1970. Juega un papel importante en el desarrollo embrionario y en la homeostasis de los tejidos al eliminar células. Una apoptosis insuficiente puede contribuir al cáncer, mientras que un exceso puede causar enfermedades autoinmunes o degenerativas.
1) Apoptosis is a tightly regulated form of programmed cell death that occurs as a normal physiological process or in pathological conditions. It is characterized by cell shrinkage, chromatin condensation, DNA fragmentation, and formation of membrane-bound apoptotic bodies that are phagocytosed without inflammation.
2) The intrinsic and extrinsic pathways regulate apoptosis through a cascade of caspase activation. The intrinsic pathway involves mitochondrial permeabilization and cytochrome c release in response to cellular stress. This activates caspase-9 and downstream executioner caspases like caspase-3. The extrinsic pathway is triggered via death receptors engaging caspase-8 and -10. Both pathways converge on caspase activation and cell dismantling.
3)
The document summarizes different types of cell death including programmed cell death (PCD), apoptosis, necrosis, and autophagy. It describes key aspects of apoptosis such as the intrinsic and extrinsic pathways, the role of caspases and Bcl-2 proteins, mitochondrial involvement, and morphological changes cells undergo during apoptosis. Necrosis is described as unprogrammed cell death caused by external factors like trauma or infection. Autophagy is noted as another form of programmed cell death.
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There are two main types of cell death: necrosis and apoptosis. Necrosis is accidental cell death due to external factors like trauma or toxins. It is characterized by cellular contents leaking out and causing inflammation. Apoptosis is programmed cell death that occurs as part of normal development and tissue homeostasis. It is triggered through internal signals or external death ligands binding to receptors. This activates a caspase cascade that breaks down the cell in a controlled, non-inflammatory way. Dysregulation of apoptosis can lead to cancer, autoimmune disease, or neurodegeneration.
Cells can die through injury or programmed cell death (apoptosis). During apoptosis, cells shrink, bleb, condense their DNA, and break into fragments that are phagocytosed. Apoptosis is triggered by the withdrawal of survival signals or receipt of death signals and involves three pathways - intrinsic/mitochondrial, extrinsic/death receptor, or apoptosis-inducing factor release. All pathways activate caspases that dismantle the cell in an orderly manner.
The document discusses various types of programmed cell death (PCD), including apoptosis, autophagy, paraptosis, autoschizis, oncosis, and necrosis. It provides details on the characteristics and mechanisms of apoptosis and autophagy. Apoptosis involves blebbing, cell shrinkage, nuclear fragmentation, and is mediated by caspases through the intrinsic and extrinsic pathways. Autophagy results in autophagosomic-lysosomal degradation of cytoplasmic contents and organelles. The document also discusses some plant-specific features of apoptosis and its role in pollen self-incompatibility.
Apoptosis is a tightly regulated process of programmed cell death that removes unnecessary or damaged cells. It is mediated by caspases, cysteine-dependent aspartate-directed proteases, that cleave key cellular proteins and lead to cell death. Apoptosis occurs through the intrinsic mitochondrial pathway or the extrinsic death receptor pathway and plays an important role in development, tissue homeostasis, and defense against infection and cancer. Defects in apoptosis can lead to neurodegenerative diseases, autoimmunity, and cancer.
This document summarizes various mechanisms of cell death, including apoptosis and necrosis. Apoptosis, or programmed cell death, involves activation of caspases through intrinsic or extrinsic pathways, leading to controlled cell death without inflammation. Necrosis occurs due to external factors causing cell membrane rupture and inflammatory cell death. Other mechanisms discussed include autophagy, which involves lysosomal degradation of cellular components, and entosis, where one cell crawls inside another to die.
This document summarizes various mechanisms of cell death, including apoptosis and necrosis. Apoptosis, or programmed cell death, involves activation of caspases through intrinsic or extrinsic pathways, leading to controlled cell death without inflammation. Necrosis occurs due to external factors causing cell membrane rupture and inflammatory cell death. Other mechanisms discussed include autophagy, which involves lysosomal degradation of cellular components, and entosis, where one cell crawls inside another to die.
This document provides an introduction to apoptosis, or programmed cell death. It discusses how apoptosis is important for homeostasis and shaping tissues during development. Apoptosis is a highly regulated process where cells self-degrade through molecular machinery like caspases. The document outlines the molecular pathways of apoptosis, including the extrinsic, intrinsic, and execution pathways. It also discusses apoptosis in animals, plants, and the roles of autophagy and caspase enzymes.
Apoptosis is a process of programmed cell death that occurs in multicellular organisms. During apoptosis, cells exhibit characteristic changes such as blebbing, shrinkage, nuclear fragmentation, and chromosomal DNA fragmentation. Between 50-70 billion cells die each day in the human body through apoptosis. Apoptosis is important for development and shaping of embryos, as well as for destroying infected, cancerous, or damaged cells. Caspases are a family of cysteine proteases that play essential roles in apoptosis. There are intrinsic and extrinsic pathways of caspase activation - the intrinsic pathway involves mitochondria and the extrinsic involves death receptors. Inhibitor of apoptosis proteins can block apoptosis and lead to conditions like cancer if unregulated.
This document discusses the molecular basis of cancer. It outlines several key cellular and molecular hallmarks of cancer, including evading apoptosis, unlimited replicative potential, sustained angiogenesis, invasion and metastasis. Specifically, it describes in detail the intrinsic and extrinsic apoptosis pathways and how cancer cells evade these pathways. It also explains how cancer cells achieve unlimited division through telomerase reactivation and avoidance of senescence and crisis. The development of angiogenesis and the multi-step process of invasion and metastasis are also summarized.
This document discusses the molecular basis of cancer. It outlines several key cellular and molecular hallmarks of cancer, including evading apoptosis, unlimited replicative potential, sustained angiogenesis, invasion and metastasis. Specifically, it describes in detail the intrinsic and extrinsic apoptosis pathways and how cancer cells evade these pathways. It also explains how cancer cells achieve unlimited division through telomerase reactivation and avoiding senescence or mitotic crisis. The development of angiogenesis in tumors and the multi-step process of metastasis are also summarized.
The document discusses apoptosis, or programmed cell death. It defines apoptosis and describes the morphological changes that occur during apoptosis, including cell shrinkage, nuclear fragmentation, and chromatin condensation. It then explains the role of caspases in apoptosis, the intrinsic and extrinsic pathways that initiate apoptosis, and the common pathway involving caspase activation that leads to apoptosis. The document concludes by discussing disorders related to improper apoptosis and references several sources for further information.
Apoptosis, or programmed cell death, is an important process by which cells self-destruct in a regulated manner. During development, apoptosis sculpted structures like fingers and toes by killing cells between them. Apoptosis also causes tissues like the tail to disappear at metamorphosis. The process is mediated by caspase proteases and regulated by Bcl-2 family proteins, with Bax and Bak activating caspases. Cells undergo apoptosis to maintain tissue homeostasis, avoid harming neighbors, and be removed by macrophages.
Apoptosis is a tightly regulated and genetically programmed process of cell death. It involves the activation of intracellular enzymes that break down nuclear DNA and proteins, breaking the cell into fragments called apoptotic bodies. There are two main pathways that trigger apoptosis - the mitochondrial pathway, which involves the release of death proteins from mitochondria, and the death receptor pathway, initiated by ligands binding to receptors on the cell surface. Both pathways activate caspases that dismantle the cell in an orderly manner, after which phagocytes remove the cellular debris.
Apoptosis is a programmed cell death process that occurs in multicellular organisms. It is an important physiological process that helps remove damaged or unnecessary cells. During apoptosis, cells shrink, condense and fragment into apoptotic bodies that are then phagocytosed and removed without triggering inflammation. Apoptosis is regulated by a network of pro- and anti-apoptotic genes and proteins and occurs through intrinsic and extrinsic pathways that activate caspase enzymes and lead to cell death. Apoptosis plays a key role in development, homeostasis, and protection against unhealthy cells.
Apoptosis, or programmed cell death, is a mechanism by which cells self-destruct in a controlled way in response to signals. During apoptosis, the cell destroys itself from within in a way that avoids releasing harmful cell contents, unlike necrosis which is cell death due to external injury. Apoptosis is important for processes like development, immunity, and cancer prevention by destroying damaged or unneeded cells. It occurs through two main pathways, the intrinsic mitochondrial pathway or the extrinsic death receptor pathway, which involve signals, cellular components like caspases, and changes inside the cell like DNA fragmentation, ultimately leading to controlled demolition of the cell.
Apoptosis, or programmed cell death, is a mechanism by which cells self-destruct in a controlled way in response to signals. During apoptosis, the cell destroys itself from within in a way that avoids releasing harmful cell contents, unlike necrosis which is cell death due to external injury. Apoptosis is important for processes like development, immunity, and cancer prevention by destroying damaged or unneeded cells. It occurs through two main pathways, the intrinsic mitochondrial pathway or the extrinsic death receptor pathway, which involve signaling cascades that activate caspase enzymes and lead to controlled breakdown of the cell.
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Abdominal trauma in pediatrics refers to injuries or damage to the abdominal organs in children. It can occur due to various causes such as falls, motor vehicle accidents, sports-related injuries, and physical abuse. Children are more vulnerable to abdominal trauma due to their unique anatomical and physiological characteristics. Signs and symptoms include abdominal pain, tenderness, distension, vomiting, and signs of shock. Diagnosis involves physical examination, imaging studies, and laboratory tests. Management depends on the severity and may involve conservative treatment or surgical intervention. Prevention is crucial in reducing the incidence of abdominal trauma in children.
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These lecture slides, by Dr Sidra Arshad, offer a quick overview of the 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 lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
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. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
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Identification and nursing management of congenital malformations .pptx
Apoptosis vs necrosis
1. ggggggggggggggg Faculty of Pharmacy
Mansoura University
Prepared by
Muhannad Soliman
2016
Biochemistry Department
Apoptosis & Necrosis and their
relationship with Cancer
2. Index
1- Introduction 2-3
2- Apoptosis 4- 6
A – Causes 4
B - Mechanism 5-6
3- Necrosis 7-8
A - Mechanism
4- Relationship with cancer 9-10
5- References 11
3. Introduction
There are two ways in which cells die:-They are killed by injurious agents or induced to commit suicide.
Death by injury Necrosis
Cells that are damaged by
injury, such as by
mechanical damage
exposure to toxic
chemicals
undergo a characteristic series
of changes:
They (and their
organelles like
mitochondria) swell
(because the ability of
the plasma membrane to
control the passage of
ions and water is
disrupted).
The cell contents leak
out, leading to
inflammation of
surrounding tissues.
Death by suicide
Apoptosis
Cells that are induced to commit suicide:
shrink; develop bubble-like blebs on their surface; have the chromatin (DNA and
protein) in their nucleus degraded; have their mitochondria break down with the
release of cytochrome c; break into small, membrane-wrapped, fragments; release
(at least in mammalian cells) ATP and UTP.
These nucleotides bind to receptors on wandering phagocytic cells like macrophages
and dendritic cells and attract them to the dying cells (a "find-me" signal").
The phospholipid phosphatidylserine, which is normally hidden in the inner layer of
the plasma membrane, is exposed on the surface.
This "eat me" signal is bound by other receptors on the phagocytes which then
engulf the cell fragments. The phagocytic cells secrete cytokines that inhibit
inflammation (e.g., IL-10 and TGF-β)
The pattern of events in death by suicide is so orderly that the process is often called
programmed cell death or PCD. The cellular machinery of programmed cell death turns out
to be as intrinsic to the cell as, say, mitosis.
Programmed cell death is also called apoptosis.
4. Apoptosis
Why should a cell commit suicide? There are two different reasons.
1. Programmed cell death is as needed for proper development as mitosis is. Examples:
The resorption of the tadpole tail at the time of its metamorphosis into a frog occurs by apoptosis.
The formation of the fingers and toes of the fetus requires the removal, by apoptosis, of the tissue
between them.
The sloughing off of the inner lining of the uterus (the endometrium) at the start of menstruation
occurs by apoptosis.
The formation of the proper connections (synapses) between neurons in the brain requires that
surplus cells be eliminated by apoptosis.
The elimination of T cells that might otherwise mount an autoimmune attack on the body occurs by
apoptosis.
During the pupal stage of insects that undergo complete metamorphosis, most of the cells of the
larva die by apoptosis thus providing the nutrients for the development of the structures of the
adult.
2. Programmed cell death is needed to destroy cells that represent a threat to the
integrity of the organism.
Examples:
Cells infected with viruses One of the methods by which cytotoxic T lymphocytes (CTLs) kill virus-infected
cells is by inducing apoptosis [diagram of the mechanism]. (And some viruses mount countermeasures to
thwart it)
Cells of the immune system As cell-mediated immune responses wane, the effector cells must be removed
to prevent them from attacking body constituents. CTLs induce apoptosis in each other and even in
themselves. Defects in the apoptotic machinery is associated with autoimmune diseases such as systemic
lupus erythematosus and rheumatoid arthritis.
Cells with DNA damage Damage to its genome can cause a cell to disrupt proper embryonic development
leading to birth defects to become cancerous.
Cells respond to DNA damage by increasing their production of p53. p53 is a potent inducer of apoptosis. Is
it any wonder that mutations in the p53 gene, producing a defective protein, are so often found in cancer
cells (that represent a lethal threat to the organism if permitted to live)
Cancer cells Radiation and chemicals used in cancer therapy induce apoptosis in some types of cancer cells.
What makes a cell decide to commit suicide?
The balance between: the withdrawal of positive signals; that is, signals needed for continued survival, and
the receipt of negative signals.
Withdrawal of positive signals The continued survival of most cells requires that they receive
continuous stimulation from other cells and, for many, continued adhesion to the surface on which they
are growing. Some examples of positive signals:
growth factors for neurons
Interleukin-2 (IL-2), an essential factor for the mitosis of lymphocytes
Receipt of negative signals
increased levels of oxidants within the cell
damage to DNA by these oxidants or other agents like ultraviolet light , X-rays , chemotherapeutic drugs
accumulation of proteins that failed to fold properly into their proper tertiary structure
molecules that bind to specific receptors on the cell surface and signal the cell to begin the
apoptosis program. These death activators include:
o Tumor necrosis factor-alpha (TNF-α) that binds to the TNF receptor;
o Lymphotoxin (also known as TNF-β) that also binds to the TNF receptor;
o Fas ligand (FasL), a molecule that binds to a cell-surface receptor named Fas (also called
CD95).
5. The Mechanisms of Apoptosis
There are 3 different mechanisms by which a cell commits suicide by apoptosis.
1. One generated by signals arising within the cell;
2. another triggered by death activators binding to receptors at the cell surface: TNF-α ,
Lymphotoxin,Fas ligand (FasL).
3. A third that may be triggered by dangerous reactive oxygen species.
1. Apoptosis triggered by internal signals: the intrinsic or mitochondrial pathway
In a healthy cell, the outer membranes of its
mitochondria display the protein Bcl-2 on their
surface. Bcl-2 inhibits apoptosis.
Internal damage to the cell
o causes a related protein, Bax, to migrate to the
surface of the mitochondrion where it inhibits the
protective effect of Bcl-2 and inserts itself into the
outer mitochondrial membrane punching holes in it
and causing cytochrome c to leak out.
The released cytochrome c binds to the protein
Apaf-1 ("apoptotic protease activating factor-1").
Using the energy provided by ATP,
these complexes aggregate to form
apoptosomes.
The apoptosomes bind to and activate caspase-9.
Caspase-9 is one of a family of over a dozen caspases. They are all proteases. They get their name
because they cleave proteins — mostly each other — at aspartic acid (Asp) residues).
Caspase-9 cleaves and, in so doing, activates other caspases (caspase-3 and -7).
The activation of these "executioner" caspases creates an expanding cascade of proteolytic activity
(rather like that in blood clotting and complement activation) which leads to digestion of structural
proteins in the cytoplasm,degradation of chromosomal DNA, and phagocytosis of the cell.
2. Apoptosis triggered by external signals: the extrinsic or death receptor pathway
Fas and the TNF receptor are integral membrane proteins with
their receptor domains exposed at the surface of the cell
binding of the complementary death activator (FasL and TNF
respectively) transmits a signal to the cytoplasm that leads to
activation of caspase 8
caspase 8 (like caspase 9) initiates a cascade of caspase activation
leading to
phagocytosis of the cell.
Example (right): When cytotoxic T cells recognize (bind to) their target,
they produce more FasL at their surface.
This binds with the Fas on the surface of the target cell leading
to its death by apoptosis.
The early steps in apoptosis are reversible — at least in C. elegans. In
some cases, final destruction of the cell is guaranteed only with its engulfment by a
phagocyte.
3. Apoptosis-Inducing Factor (AIF)
Neurons, and perhaps other cells, have another way to self-destruct that — unlike the two paths described
above — does not use caspases.
Apoptosis-inducing factor (AIF) is a protein that is normally located in the intermembrane space of
mitochondria. When the cell receives a signal telling it that it is time to die, AIF
is released from the mitochondria (like the release of cytochrome c in the first pathway);
migrates into the nucleus; binds to DNA, which triggers the destruction of the DNA and cell death.
6.
7. Apoptosis and Cancer
Some viruses associated with cancers use tricks to prevent apoptosis of the cells they have transformed.
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
o produces a protein similar to Bcl-2
o 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).
Even cancer cells produced without the participation of viruses may have tricks to avoid apoptosis.
Some B-cell leukemias and lymphomas express high levels of Bcl-2, thus blocking apoptotic signals
they may receive. The high levels result from a translocation of the BCL-2 gene into an enhancer
region for antibody production.
Melanoma (the most dangerous type of skin cancer) cells avoid apoptosis by inhibiting the
expression of the gene encoding Apaf-1.
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 .
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).
8. Necrosis is the prominent mode of cell death that occurs in various neurodegenerative
conditions and as a consequence to ischemic injury in various organs including the brain
and heart.
Although progress has been made in the last decade in understanding the molecular
mechanisms of apoptosis, the biochemical pathways leading to necrotic cell death remain
poorly understood.
Necrosis has long been thought to be a “passive” process occurring as a consequence of
acute ATP depletion. Several ATP-dependent ion channels become ineffective, leading to
ion dyshomeostasis, disruption of the actin cytoskeleton, cell swelling, membrane blebbing,
and eventual collapse of the cell .
Recent reports suggest that in addition to the passive mechanisms, “active” mechanisms,
such as Na+
overloading, Ca2+
accumulation, and changes in mitochondrial permeability,
may also participate in the necrotic process
9. Sequence of biochemical events that may lead to necrotic cell death
1- In ischemic or hypoxic injury, energy depletion occurs by defective ATP production combined with the
rapid consumption of ATP by ion pumps and through hydrolysis and leakage.
The necrotic volume increase associated with necrotic cell death is initiated by an influx of Na+ and release
of ATP due to membrane leakage.
The increased Na+ level in the cytosol
activates Na+-K+-ATPase, resulting in
dissipation of ATP.
In the beginning stages of the injury, a
simultaneous efflux of K+ maintains
ion homeostasis. Severe depletion of
ATP leads to failure of the pump-leak
balance mechanism, leading to an
influx of Na+ and water that results in
swelling and collapse of the cell. Thus
the overload of Na+ concomitant with
severe ATP depletion seems to be the
major determinant of a necrotic
outcome.
2- Cytosolic Ca2+ plays a role in linking ATP depletion and necrosis in some cell types, but several other cell
types including hepatocytes and renal tubules can undergo necrotic cell death in its absence.
The reactive oxygen species-mediated necrotic volume increase and Na+ influx are suggested to be
initiated by the binding of the free radicals to ion channels including nonselective Ca2+ channels.
The increased levels of Na+ activate Na+-K+-ATPase and consume ATP, which, in turn, activates nonselective
Ca2+ channels, resulting in massive cytosolic Ca2+ accumulation. High levels of Ca2+ can participate in ATP
depletion by activating Ca2+-ATPase and mitochondrial depolarization.
The increased levels of Ca2+ activate endonucleases to degrade DNA and activate cellular proteases such as
calpain to degrade several structural and signaling proteins.
3-Mitochondria participate in necrotic as well as apoptotic cell death by opening the mitochondrial
permeability transition pore. an essential role of the mitochondrial permeability transition (MPT) in the
release of cytochrome c and initiation of apoptosis in many models, including hepatocytes exposed to TNF-
α and Fas ligation.
Several second messengers and proapoptotic proteins including Bcl-2 family members can induce the
permeabilization of the MPT pore.BNIP3 is a member of the Bcl-2 family that is loosely associated with
mitochondria in the normal state but gets fully integrated into the mitochondrial outer membrane after a
death stimulus. BNIP3-transfected cells are found to undergo cell death independently of Apaf-1, caspase
activation, cytochrome c release, and nuclear translocation of apoptosis-inducing factor. The cells
exhibited morphology typical of the necrotic form of cell death with plasma membrane permeability,
mitochondrial damage, extensive cytoplasmic vacuolation, and mitochondrial autophagy.
It is proposed that BNIP3 can mediate necrosislike cell death through mitochondrial permeability transition
pore opening and mitochondrial dysfunction.The expression of BNIP3 is shown to be induced in several cell
lines in response to hypoxic injury. Overexpression of the hypoxia-inducible factor-1α has also been shown
to induce the expression of BNIP3, resulting in a necrotic form of cell death.Moreover, although ischemia-
reperfusion is usually associated with necrotic cell death,more recent studies have shown that apoptosis
also occurs after ischemia-reperfusion in cells from liver and other organs.
10.
11. Necrosis in tumorigenesis
Tumor cell necrosis can provoke an inflammatory response, and stimulate an immune response towards
potentially malignant cells. In this case, necrosis might prevent tumor development. Experiments with
TNFa support this notion.
TNFa is originally isolated as an anti-cancer cytokine, able to kill tumor cells and to induce tumor
regression in mice. On the other hand, mice with impaired TNFa signaling, such as TNFa-/- and TNFR1-/-
mice, are less prone to develop tumors in inducible tumor mouse models. It thus follows that TNFa can
also promote tumorigenesis.
It has been proposed that chronic inflammation, in contrast to an acute inflammatory response, can
promote tumor development.
In agreement with the latter, patients with chronic inflammatory bowel diseases (IBD) have an increased
risk of cancer development,and patients with the familial adenomatous polyposis (FAP) syndrome show a
significant reduction in the number and size of colorectal adenomas upon treatment with the anti-
inflammatory drugs celecoxib. Since necrosis can lead to inflammation and a sustained inflammatory
response can stimulate tumor development, these data provide some indirect evidence for a role of
necrosis in tumor development.
Necrosis in cancer treatment
-necrosis is induced by anti-cancer drugs, particularly by DNA-alkylating drugs. DNA-alkylating agents have
shown to cause necrotic cell death via activation of PARP-1. This necrosis occurs with equal effectiveness in
cells with or without functional apoptosis.
Interestingly, especially cells using aerobic glycolysis are shown to be sensitive for this PARP-mediated
necrosis.
Since many tumor cells depend on aerobic glycolysis, this observation suggests that tumor cells in
particular might be killed through necrosis upon treatment with alkylating agents.
- chemotherapy induces more necrotic than apoptotic cell death in breast cancer patients, and this
necrotic response is associated with a better survival.
- PARP-dependent necrosis is also associated with TNF receptor–independent activation of RIPK1, TRAF2,
and downstream effector c-Jun NH2-terminal kinase.
The bioenergetic crisis that occurs with acute NAD+ and ATP depletion in glycolytic cells is associated with
the accumulation of high concentrations of intracellular calcium and ROS , which in turn cooperate to
activate Ca2+-dependent cytosolic proteases calpains.
Activated calpains cleave Ca2+extrusion channels and permeabilize lysosomes, leaking executioner
cathepsins.
High intracellular calcium concentrations and ROS also activate phospholipase A2.
Proteolysis and lipid peroxidation ensues, leading to widespread membrane permeabilization and
irreversible necrotic cell death.
12. References
1. Barry, M.A., Behnike C.A., Eastman A., Activation of programmed
cell death (apoptosis) by cisplatin, other anticancer drugs, toxins and
hyperthermia, Biochem. Pharmacol., 1990, 40, 2353–2362.
2.Carswell EA, Old LJ, Kassel RL, et al . An endotoxin-induced
serum factor that causes necrosis of tumors. Proc Natl Acad Sci
USA 1975; 72: 3666–3670.
3. Green S, Dobrjansky A, Carswell EA, et al . Partial purification of
a serum factor that causes necrosis of tumors. Proc Natl Acad SciUSA
1976; 73: 381–385.
4. http://www.biology-pages.info/A/Apoptosis.html
5. Proskuryov SY, et al. Necrosis: a specific form of programmed cell
death? Exp. Cell Res. 2003;283:1–16. [PubMed]
6. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC420517/