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DNA Repair Mechanisms and Oxidative Stress
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DNA Repair Mechanisms and Oxidative Stress

Created by
@CleanlyBoston

Questions and Answers

Which enzyme converts O₂ − into H₂O₂ and O₂?

  • Catalase
  • Superoxide Dismutase (correct)
  • NADPH Oxidase
  • Glutathione Peroxidase

    • What reaction converts H₂O₂ into a hydroxyl radical in the presence of iron?

  • Catalytic oxidation
  • Fenton reaction (correct)
  • Haber-Weiss reaction
  • Schlenk equilibrium

    • Which of the following antioxidants can directly scavenge free radicals?

  • Ascorbic acid (correct)
  • Calcium
  • Selenium
  • Vitamin D

    • What is the primary effect of lipid peroxidation caused by reactive oxygen species?

    <p>Compromised membrane integrity</p> Signup and view all the answers

    Which protein is responsible for sequestering iron and preventing free radical formation?

    <p>Transferrin</p> Signup and view all the answers

    Which of the following free radicals is converted into the peroxynitrite anion (ONOO⁻)?

    <p>Nitric oxide (NO)</p> Signup and view all the answers

    Which DNA repair mechanism is primarily activated during cell cycle arrest to correct extensive DNA damage?

    <p>Nucleotide excision repair</p> Signup and view all the answers

    What is the primary role of catalase in cellular defense against oxidative damage?

    <p>Decomposes hydrogen peroxide into water and oxygen</p> Signup and view all the answers

    What role does p53 play if the DNA damage cannot be repaired?

    <p>Initiates apoptosis</p> Signup and view all the answers

    How do mutations in the p53 gene influence cancer development?

    <p>They allow cells with damaged DNA to divide</p> Signup and view all the answers

    What type of damage can free radicals cause to proteins?

    <p>Oxidative modification of amino acid side chains</p> Signup and view all the answers

    Which of the following best describes the effect of reactive oxygen species (ROS) on cells?

    <p>They attack and modify essential molecules</p> Signup and view all the answers

    During which normal metabolic process are free radicals, such as superoxide anion and hydrogen peroxide, primarily generated?

    <p>Cellular respiration</p> Signup and view all the answers

    What is one of the main effects of oxidative stress due to the accumulation of oxygen-derived free radicals?

    <p>Cellular aging and injury</p> Signup and view all the answers

    What can cause the formation of free radicals through the hydrolysis of water?

    <p>Radiant energy like UV light</p> Signup and view all the answers

    Which statement is true regarding the protective role of apoptosis in the context of DNA damage?

    <p>Apoptosis prevents the proliferation of potentially oncogenic cells</p> Signup and view all the answers

    What is the primary effect of phospholipases activated by elevated Ca²⁺ levels?

    <p>Breakdown of membrane phospholipids</p> Signup and view all the answers

    In the context of ischemia, what happens to ATP production compared to hypoxia?

    <p>ATP production is completely halted.</p> Signup and view all the answers

    How do Ca²⁺-activated proteases affect the cell?

    <p>They degrade structural proteins, compromising cell integrity.</p> Signup and view all the answers

    What is the role of Hypoxia-Inducible Factor-1 (HIF-1) during hypoxic conditions?

    <p>To promote angiogenesis and enhance glycolysis.</p> Signup and view all the answers

    What distinguishes ischemia from hypoxia?

    <p>Ischemia results from reduced blood flow, not limited oxygen.</p> Signup and view all the answers

    What immediate cellular injury occurs due to ATP depletion?

    <p>Reversible cell and organelle swelling.</p> Signup and view all the answers

    What is a consequence of the activation of ATPases due to increased Ca²⁺ levels?

    <p>Accelerated depletion of cellular energy reserves.</p> Signup and view all the answers

    What is the effect of endonucleases during cellular injury?

    <p>They fragment DNA and chromatin.</p> Signup and view all the answers

    What is the main purpose of therapeutic hypothermia in ischemic brain and spinal cord injury?

    <p>To reduce metabolic demands and minimize cell injury.</p> Signup and view all the answers

    Which of the following best describes the paradoxical effect of reperfusion injury?

    <p>Blood flow restoration can lead to further damage through several mechanisms.</p> Signup and view all the answers

    What role does oxidative stress play during reperfusion injury?

    <p>It generates reactive oxygen species that can further damage cells.</p> Signup and view all the answers

    What happens to intracellular calcium levels during reperfusion?

    <p>They increase, exacerbating calcium overload from ischemia.</p> Signup and view all the answers

    What triggers inflammation during ischemia?

    <p>The release of 'danger signals' from dead cells and cytokine secretion.</p> Signup and view all the answers

    How does the complement system exacerbate cell injury during reperfusion?

    <p>By binding to IgM antibodies deposited in ischemic tissues.</p> Signup and view all the answers

    Which organ is notably affected by chemical injuries due to its role in drug metabolism?

    <p>Liver</p> Signup and view all the answers

    What is NOT a consequence of oxidative stress during reperfusion?

    <p>Reinforcement of antioxidant defenses.</p> Signup and view all the answers

    What role do reactive oxygen species (ROS) play in DNA damage?

    <p>They induce single and double-strand breaks and may contribute to cellular aging.</p> Signup and view all the answers

    How does calcium normally function as a signaling molecule in cells?

    <p>By acting as a second messenger in various cellular signaling pathways.</p> Signup and view all the answers

    What is the main consequence of elevated cytosolic Ca²⁺ levels?

    <p>Contributing to cell injury through mitochondrial damage.</p> Signup and view all the answers

    What physiological condition can lead to an increase in cytosolic Ca²⁺?

    <p>Ischemia and the exposure to certain toxins.</p> Signup and view all the answers

    Which mechanism contributes to mitochondrial damage from calcium disturbance?

    <p>Failure of ATP generation due to mitochondrial permeability transition.</p> Signup and view all the answers

    What helps maintain low cytosolic Ca²⁺ concentrations under normal conditions?

    <p>Active transport mechanisms pumping Ca²⁺ into cellular stores.</p> Signup and view all the answers

    What is a likely outcome of impaired calcium homeostasis during ischemia?

    <p>Release of intracellular calcium stores elevating cytosolic concentration.</p> Signup and view all the answers

    How do reactive oxygen species (ROS) and elevated calcium ions interact in the context of cell injury?

    <p>High calcium levels lead to increased ROS generation, compounding cellular damage.</p> Signup and view all the answers

    Activated leukocytes produce ROS primarily through the activity of NADPH oxidase.

    <p>True</p> Signup and view all the answers

    Carbon tetrachloride (CCl₄) is an endogenous chemical that cannot be converted into free radicals.

    <p>False</p> Signup and view all the answers

    The Fenton reaction involves the conversion of hydrogen peroxide (H₂O₂) into a free radical in the presence of copper ions.

    <p>False</p> Signup and view all the answers

    Free radicals can spontaneously dismutate, such as O₂ − converting into O₂ and H₂O₂.

    <p>True</p> Signup and view all the answers

    Antioxidants work by enhancing the formation of free radicals in the body.

    <p>False</p> Signup and view all the answers

    Lipid peroxidation caused by ROS compromises the integrity of cell membranes.

    <p>True</p> Signup and view all the answers

    Glutathione Peroxidase reduces hydrogen peroxide to generate reactive oxygen species.

    <p>False</p> Signup and view all the answers

    Ischemia allows for full anaerobic metabolism to continue, similar to hypoxia.

    <p>False</p> Signup and view all the answers

    Reactive species like peroxynitrite can convert nitric oxide into free radicals.

    <p>True</p> Signup and view all the answers

    Increased levels of Ca²⁺ activate endonucleases, leading to fragmentation of DNA.

    <p>True</p> Signup and view all the answers

    Phospholipases degrade cytoskeletal proteins primarily by acting on ATP molecules.

    <p>False</p> Signup and view all the answers

    Hypoxia-inducible factor-1 (HIF-1) activation is initiated by decreases in oxygen levels.

    <p>True</p> Signup and view all the answers

    Prolonged ischemia can initially cause reversible cell injury due to maintenance of ATP levels.

    <p>False</p> Signup and view all the answers

    The activation of ATPases by increased Ca²⁺ levels leads to a decrease in cellular ATP consumption.

    <p>False</p> Signup and view all the answers

    Oxygen deprivation during ischemia affects oxidative phosphorylation in mitochondria.

    <p>True</p> Signup and view all the answers

    Ischemia is characterized by maintained blood flow with limited oxygen delivery to tissues.

    <p>False</p> Signup and view all the answers

    DNA damage repair mechanisms are only activated during cell cycle progression.

    <p>False</p> Signup and view all the answers

    P53 is responsible for initiating apoptosis only if DNA damage is minor.

    <p>False</p> Signup and view all the answers

    Reactive oxygen species (ROS) can form during both normal metabolic processes and due to radiant energy.

    <p>True</p> Signup and view all the answers

    Mutations in the p53 gene can enhance the ability of cells with damaged DNA to undergo apoptosis.

    <p>False</p> Signup and view all the answers

    Free radicals primarily cause cell injury by altering essential molecules, which can lead to various pathological conditions.

    <p>True</p> Signup and view all the answers

    Therapeutic hypothermia involves raising the body’s core temperature to about 92°F.

    <p>False</p> Signup and view all the answers

    Reperfusion injury can lead to further damage due to oxidative stress and inflammation.

    <p>True</p> Signup and view all the answers

    The mitochondrial pathway for apoptosis is activated by p53 in response to minor DNA damage.

    <p>False</p> Signup and view all the answers

    During ischemia, calcium levels decrease significantly in cells.

    <p>False</p> Signup and view all the answers

    Superoxide anions ($O_2^-$) are a type of reactive oxygen species generated during cellular respiration.

    <p>True</p> Signup and view all the answers

    Oxidative stress is primarily caused by the accumulation of non-reactive species in cells.

    <p>False</p> Signup and view all the answers

    The complement system is activated by IgM antibodies during ischemic conditions, which worsens cell injury upon reperfusion.

    <p>True</p> Signup and view all the answers

    Chemical injury predominantly affects the kidneys due to their role in drug metabolism.

    <p>False</p> Signup and view all the answers

    The influx of calcium during reperfusion helps in maintaining mitochondrial function.

    <p>False</p> Signup and view all the answers

    Therapeutic hypothermia enhances metabolic demands and promotes swelling.

    <p>False</p> Signup and view all the answers

    Reactive oxygen species (ROS) are predominantly generated when blood flow is interrupted to tissues.

    <p>False</p> Signup and view all the answers

    Direct toxicity of chemicals in cells primarily damages membrane structures and ion transport mechanisms.

    <p>True</p> Signup and view all the answers

    Cyanide primarily affects the liver by enhancing the activity of cytochrome P-450 enzymes.

    <p>False</p> Signup and view all the answers

    Carbon Tetrachloride is metabolically converted in the liver to a non-toxic compound that protects cells from damage.

    <p>False</p> Signup and view all the answers

    Reversible cell injury is characterized by irreversible structural changes that cannot be corrected.

    <p>False</p> Signup and view all the answers

    The earliest sign of cellular injury is cellular swelling due to loss of fluid and ion balance.

    <p>True</p> Signup and view all the answers

    Chemotherapeutic agents can cause direct toxicity by damaging targeted cells through cytotoxic mechanisms.

    <p>True</p> Signup and view all the answers

    The primary mechanism of liver injury caused by acetaminophen is its conversion to a harmless metabolite.

    <p>False</p> Signup and view all the answers

    Increased membrane permeability is a direct consequence of cell injury caused by mercuric chloride poisoning.

    <p>True</p> Signup and view all the answers

    What triggers apoptosis in response to DNA damage, and why is this process crucial for cellular health?

    <p>Apoptosis is triggered by the p53 protein when DNA damage is extensive and irreparable, preventing the proliferation of potentially oncogenic cells.</p> Signup and view all the answers

    Describe the relationship between p53 mutations and cancer progression.

    <p>Mutations in the p53 gene impair its ability to arrest the cell cycle and induce apoptosis, allowing damaged cells to continue dividing and contributing to tumor formation.</p> Signup and view all the answers

    How do reactive oxygen species (ROS) cause cellular injury?

    <p>ROS induce cell injury by damaging essential molecules such as proteins, lipids, carbohydrates, and nucleic acids through oxidation.</p> Signup and view all the answers

    What are the primary sources of free radicals in the body, and how do they form?

    <p>Free radicals primarily originate from normal metabolic processes during cellular respiration and from exposure to radiant energy like UV light.</p> Signup and view all the answers

    Explain how the failure of DNA repair mechanisms can impact cellular function.

    <p>Failure to repair DNA can lead to the accumulation of mutations, resulting in cellular dysfunction or the initiation of apoptosis to prevent damaged cells from replicating.</p> Signup and view all the answers

    Discuss the role of free radicals in the pathogenesis of ischemia-reperfusion injury.

    <p>Free radicals contribute to ischemia-reperfusion injury by inducing oxidative stress, damaging cellular components, and triggering inflammatory responses.</p> Signup and view all the answers

    What is the significance of nucleotide and base excision repair mechanisms in preserving genomic integrity?

    <p>Nucleotide and base excision repair mechanisms correct specific types of DNA damage, which is essential for maintaining genomic stability and preventing mutations.</p> Signup and view all the answers

    What role do antioxidants play in neutralizing the effects of oxidative stress?

    <p>Antioxidants scavenge free radicals and reactive oxygen species, thereby reducing oxidative damage to cells and maintaining cellular function.</p> Signup and view all the answers

    What process is disrupted first during ischemia due to oxygen deprivation?

    <p>Oxidative phosphorylation in mitochondria ceases.</p> Signup and view all the answers

    How do proteases activated by elevated Ca²⁺ levels compromise cell integrity?

    <p>They degrade cytoskeletal and membrane proteins.</p> Signup and view all the answers

    Explain the difference in ATP production between hypoxia and ischemia.

    <p>In hypoxia, blood flow is maintained allowing some ATP production, while ischemia cuts off blood supply entirely, halting ATP production.</p> Signup and view all the answers

    What types of DNA damage can reactive oxygen species (ROS) induce?

    <p>ROS can cause single and double-strand breaks, cross-linking of DNA strands, and the formation of DNA adducts.</p> Signup and view all the answers

    How do normal cytosolic Ca²⁺ concentrations compare to extracellular levels?

    <p>Normal cytosolic Ca²⁺ levels are approximately 0.1 μmol, while extracellular levels are around 1.3 mmol.</p> Signup and view all the answers

    What role does hypoxia-inducible factor-1 (HIF-1) play in cellular adaptation to hypoxia?

    <p>HIF-1 promotes angiogenesis, enhances glycolysis, and stimulates survival pathways.</p> Signup and view all the answers

    What role does elevated cytosolic Ca²⁺ play in cell injury?

    <p>Elevated cytosolic Ca²⁺ contributes to cell injury by leading to mitochondrial damage and failure of ATP generation.</p> Signup and view all the answers

    What is the consequence of prolonged ATP depletion in tissues experiencing ischemia?

    <p>It leads to irreversible cell injury and cell death by necrosis.</p> Signup and view all the answers

    What mechanisms are disrupted that lead to abnormal increases in cytosolic Ca²⁺?

    <p>Ischemia and exposure to certain toxins disrupt calcium homeostasis, causing Ca²⁺ release from stores and increased influx across the plasma membrane.</p> Signup and view all the answers

    Describe one immediate effect caused by the activation of ATPases in cells with elevated Ca²⁺ levels.

    <p>They consume ATP at a faster rate, exacerbating energy depletion.</p> Signup and view all the answers

    What is the impact of endonucleases during cellular injury in a high calcium environment?

    <p>Endonucleases fragment DNA and chromatin.</p> Signup and view all the answers

    What is the primary function of calcium as a signaling molecule in cells?

    <p>Calcium acts as an essential second messenger regulating muscle contraction, neurotransmitter release, and cell proliferation.</p> Signup and view all the answers

    What cellular adaptations occur when oxygen levels decrease due to hypoxia?

    <p>Cells activate HIF-1, leading to increased angiogenesis and enhanced glycolysis.</p> Signup and view all the answers

    Describe the consequence of mitochondrial permeability transition pore failure due to excessive Ca²⁺ accumulation.

    <p>Failure of the mitochondrial permeability transition pore leads to impaired ATP generation essential for cell survival.</p> Signup and view all the answers

    Explain the physiological conditions that can lead to increased cytosolic Ca²⁺ levels.

    <p>Conditions such as ischemia, which leads to lack of blood supply, can cause increased cytosolic Ca²⁺ levels.</p> Signup and view all the answers

    Why are ROS considered both harmful and beneficial in cellular signaling?

    <p>While ROS can induce apoptosis and contribute to cellular damage, they also play important roles in cellular signaling when produced in controlled amounts.</p> Signup and view all the answers

    What is the role of metal binding proteins in preventing free radical formation?

    <p>Metal binding proteins sequester iron and copper, preventing them from catalyzing harmful free radical reactions.</p> Signup and view all the answers

    Describe one pathological effect of oxidative modification of proteins.

    <p>Oxidative modification can lead to enzyme inactivation and structural disruption of proteins.</p> Signup and view all the answers

    How can nitric oxide (NO) contribute to oxidative stress?

    <p>Nitric oxide can act as a free radical and be converted into reactive species like peroxynitrite, enhancing oxidative damage.</p> Signup and view all the answers

    Explain how antioxidants prevent the formation of free radicals.

    <p>Antioxidants neutralize free radicals by donating electrons, thereby stabilizing them and preventing cellular damage.</p> Signup and view all the answers

    What is lipid peroxidation, and why is it harmful to cells?

    <p>Lipid peroxidation is the oxidative degradation of lipids, leading to compromised cell membrane integrity and cellular dysfunction.</p> Signup and view all the answers

    In the context of the Fenton reaction, what role does Fe²⁺ have in free radical generation?

    <p>Fe²⁺ catalyzes the conversion of hydrogen peroxide (H₂O₂) into hydroxyl radicals (•OH), contributing to oxidative stress.</p> Signup and view all the answers

    How do superoxide dismutases (SODs) contribute to cellular defense against free radicals?

    <p>SODs convert superoxide anions (O₂ −) into hydrogen peroxide (H₂O₂) and oxygen, reducing oxidative stress.</p> Signup and view all the answers

    What is the significance of spontaneous decay of free radicals in cellular environments?

    <p>Spontaneous decay helps to reduce the overall concentration of free radicals, mitigating potential cellular damage.</p> Signup and view all the answers

    What are the main therapeutic benefits of induced hypothermia in cases of ischemic injury?

    <p>Induced hypothermia reduces metabolic demands, decreases swelling, suppresses free radical formation, and inhibits inflammatory responses.</p> Signup and view all the answers

    Explain how reperfusion injury can paradoxically lead to further tissue damage after blood flow is restored.

    <p>Reperfusion injury can lead to oxidative stress and calcium overload, causing additional cell injury despite the restoration of blood flow.</p> Signup and view all the answers

    What is the role of free radicals generated during reperfusion in the context of ischemic tissue damage?

    <p>Free radicals lead to oxidative stress, which exacerbates cell injury by damaging cellular components.</p> Signup and view all the answers

    Describe the implications of intracellular calcium overload during the reperfusion of ischemic tissues.

    <p>Calcium overload leads to the opening of the mitochondrial permeability transition pore, depleting ATP and resulting in additional cell injury.</p> Signup and view all the answers

    What inflammatory responses are triggered during ischemia and how do they contribute to reperfusion injury?

    <p>Ischemia triggers the release of danger signals and cytokines, attracting neutrophils to the area, which exacerbates tissue damage.</p> Signup and view all the answers

    How does the complement system exacerbate injury during reperfusion of ischemic tissues?

    <p>Activation of the complement system occurs when complement proteins bind to antibodies deposited in ischemic tissues, increasing inflammation and injury.</p> Signup and view all the answers

    In terms of chemical injury, why is the liver particularly vulnerable due to its role in drug metabolism?

    <p>The liver is at high risk for chemical injury because it is heavily involved in processing drugs and filtering toxins, making it susceptible to damage.</p> Signup and view all the answers

    What mechanisms of injury occur due to oxidative stress during reperfusion, and how can they hinder recovery?

    <p>Mechanisms of injury include the formation of reactive oxygen species and damage to cellular structures, which can hinder healing and recovery.</p> Signup and view all the answers

    Phospholipases are activated by elevated ______ levels.

    <p>Ca²⁺</p> Signup and view all the answers

    The absence of blood flow in ______ prevents both aerobic and anaerobic metabolism.

    <p>ischemia</p> Signup and view all the answers

    Hypoxia-Inducible Factor-1 (HIF-1) promotes ______ in response to hypoxia.

    <p>angiogenesis</p> Signup and view all the answers

    Increased Ca²⁺ levels lead to the activation of ______, causing energy depletion.

    <p>ATPases</p> Signup and view all the answers

    Prolonged ischemia results in irreversible injury and cell death through ______.

    <p>necrosis</p> Signup and view all the answers

    Endonucleases fragment ______ and chromatin, disrupting cellular function.

    <p>DNA</p> Signup and view all the answers

    Ischemia differs from hypoxia in that it completely cuts off the ______ to tissues.

    <p>blood supply</p> Signup and view all the answers

    Cellular ATP depletion initially causes ______ cell injury.

    <p>reversible</p> Signup and view all the answers

    Activated leukocytes produce ROS primarily through the activity of ______.

    <p>NADPH oxidase</p> Signup and view all the answers

    Carbon tetrachloride (CCl₄) can be metabolized into the free radical ______.

    <p>CCl₃</p> Signup and view all the answers

    The Fenton reaction involves the conversion of hydrogen peroxide (H₂O₂) into a hydroxyl radical in the presence of ______.

    <p>iron</p> Signup and view all the answers

    Non-enzymatic antioxidants, such as vitamins E and A, can ______ free radicals.

    <p>neutralize</p> Signup and view all the answers

    Lipid peroxidation can compromise membrane integrity, leading to ______ dysfunction.

    <p>cellular</p> Signup and view all the answers

    Superoxide dismutases (SODs) convert O₂ − into H₂O₂ and ______.

    <p>O₂</p> Signup and view all the answers

    Proteins like transferrin and ferritin sequester iron, preventing it from catalyzing ______ reactions.

    <p>free radical</p> Signup and view all the answers

    Glutathione peroxidase reduces hydrogen peroxide and protects cells from ______ damage.

    <p>oxidative</p> Signup and view all the answers

    ROS can cause single and double-strand breaks in ______, cross-linking of DNA strands, and the formation of DNA adducts.

    <p>DNA</p> Signup and view all the answers

    Calcium ions (Ca²⁺) act as essential second messengers in various cellular ______ pathways.

    <p>signaling</p> Signup and view all the answers

    Under normal conditions, the concentration of free Ca²⁺ in the cytosol is kept very low (~0.1 μmol) compared to extracellular ______ (~1.3 mmol).

    <p>levels</p> Signup and view all the answers

    Ionic disturbances, such as ischemia, can lead to an abnormal increase in cytosolic ______.

    <p>Ca²⁺</p> Signup and view all the answers

    Excessive Ca²⁺ accumulation in the ______ can lead to failure of ATP generation, which is critical for cell survival.

    <p>mitochondria</p> Signup and view all the answers

    Cells maintain low cytosolic Ca²⁺ through active transport mechanisms that pump Ca²⁺ into the endoplasmic ______ and mitochondria.

    <p>reticulum</p> Signup and view all the answers

    Control of cytosolic Ca²⁺ is essential for regulating processes like muscle contraction and ______ release.

    <p>neurotransmitter</p> Signup and view all the answers

    When produced in controlled amounts, ROS can serve important ______ functions in cellular signaling pathways.

    <p>physiological</p> Signup and view all the answers

    Therapeutic ______ involves lowering the body’s core temperature to minimize cell injury during ischemic events.

    <p>hypothermia</p> Signup and view all the answers

    Reperfusion injury occurs when blood flow is restored to ______ tissue.

    <p>ischemic</p> Signup and view all the answers

    Oxidative stress is characterized by the generation of ______ oxygen and nitrogen species (ROS/RNS) during reperfusion.

    <p>reactive</p> Signup and view all the answers

    During reperfusion, there is an influx of ______ into cells, leading to calcium overload.

    <p>calcium</p> Signup and view all the answers

    The complement system's activation can exacerbate ______ injury and inflammation during reperfusion.

    <p>cell</p> Signup and view all the answers

    Chemical injury often significantly affects the ______ due to its essential role in drug metabolism.

    <p>liver</p> Signup and view all the answers

    The inflammatory response during ischemia is characterized by the release of 'danger ______' from dead cells.

    <p>signals</p> Signup and view all the answers

    Blocking cytokines or adhesion molecules has been shown to reduce ______ and injury during reperfusion.

    <p>inflammation</p> Signup and view all the answers

    Toxic liver injury is a common reason for discontinuing or halting the development of certain ______.

    <p>drugs</p> Signup and view all the answers

    Mercuric Chloride Poisoning primarily affects cells involved in absorption, excretion, or ______ of chemicals.

    <p>concentration</p> Signup and view all the answers

    Cyanide inhibits mitochondrial cytochrome oxidase, blocking oxidative ______ and leading to cell death.

    <p>phosphorylation</p> Signup and view all the answers

    Many chemicals become toxic after being metabolized into reactive toxic ______.

    <p>metabolites</p> Signup and view all the answers

    Cellular swelling is the earliest sign of almost all types of cell ______.

    <p>injury</p> Signup and view all the answers

    CCl₄ is converted by cytochrome P-450 enzymes into the reactive free radical ______.

    <p>CCl₃</p> Signup and view all the answers

    Reversible cell injury can be corrected if the harmful ______ is removed.

    <p>stimulus</p> Signup and view all the answers

    Acetaminophen is metabolized in the liver to a toxic product that can cause significant liver ______.

    <p>injury</p> Signup and view all the answers

    Match the following DNA repair mechanisms with their primary functions:

    <p>Nucleotide excision repair = Removes bulky DNA adducts Base excision repair = Corrects small, non-helix-distorting base lesions Double-strand break repair = Restores integrity of broken DNA strands Apoptosis from p53 = Eliminates cells with substantial DNA damage</p> Signup and view all the answers

    Match the following oxidative stress sources with their effects:

    <p>Molecular oxygen (O₂) = Produces superoxide anion (O₂ −) Ultraviolet light = Hydrolyzes water into hydroxyl radicals Radiation exposure = Generates various free radicals Cellular respiration = Produces hydrogen peroxide (H₂O₂)</p> Signup and view all the answers

    Match the following outcomes of failed DNA repair with their implications:

    <p>Induction of apoptosis = Prevents proliferation of potentially oncogenic cells Survival of damaged cells = Increases likelihood of tumor formation p53 mutations = Impair cell cycle arrest function Apoptosis triggered by p53 = Acts as a protective mechanism</p> Signup and view all the answers

    Match the following free radicals with their forms in metabolic processes:

    <p>Superoxide anion = O₂ − Hydrogen peroxide = H₂O₂ Hydroxyl radical = •OH Reactive oxygen species = ROS</p> Signup and view all the answers

    Match the following types of DNA damage with their repair responses:

    <p>Bulky adducts = Nucleotide excision repair Single-strand breaks = Base excision repair Double-strand breaks = Homologous recombination or non-homologous end joining Base mismatches = Mismatch repair</p> Signup and view all the answers

    Match the following consequences of oxidative stress to their associated processes:

    <p>Chemical injury = Promotes free radical generation Cellular aging = Increases oxidative damage accumulation Microbial killing = Utilizes free radicals for defense Radiation injury = Leads to significant cellular damage</p> Signup and view all the answers

    Match the following p53 functions with their roles in cell cycle regulation:

    <p>Cell cycle arrest = Allows time for DNA repair Induction of apoptosis = Prevents survival of damaged cells Regulation of cellular stress response = Response to DNA damage Prevention of tumor formation = Eliminates potentially cancerous cells</p> Signup and view all the answers

    Match the following free radicals to their generation pathways:

    <p>Superoxide = Produced during electron transport chain Hydrogen peroxide = Generated from superoxide dismutation Hydroxyl radical = Formed via Fenton reaction Nitric oxide = Can react with superoxide to form peroxynitrite</p> Signup and view all the answers

    Match the following conditions with their potential effects on calcium homeostasis:

    <p>Ischemia = Increased intracellular Ca²⁺ levels Toxins = Release of Ca²⁺ from intracellular stores Normal conditions = Maintained low cytosolic Ca²⁺ concentration Excessive Ca²⁺ = Mitochondrial damage and ATP failure</p> Signup and view all the answers

    Match the following physiological roles of calcium with their descriptions:

    <p>Muscle contraction = Directly influenced by Ca²⁺ levels Neurotransmitter release = Ca²⁺ acts as a second messenger Cell proliferation = Regulated by cytosolic Ca²⁺ Mitochondrial function = Involves Ca²⁺ in energy production</p> Signup and view all the answers

    Match the following types of DNA damage with their characteristics:

    <p>Single-strand breaks = Repairable with lower risk of cancer Double-strand breaks = More severe and associated with higher cancer risk Cross-linking = Prevents separation during replication DNA adducts = Modification by reactive species</p> Signup and view all the answers

    Match the following reactive oxygen species (ROS) interactions with their outcomes:

    <p>Excessive ROS = Cell injury and apoptosis induction Controlled ROS production = Physiological signaling Lipid peroxidation = Membrane integrity compromise ROS interaction with DNA = Mutation and cancer development</p> Signup and view all the answers

    Match the disturbances of calcium homeostasis with their mechanisms:

    <p>Increased influx across plasma membrane = Damaged membrane channels and transporters Release from ER and mitochondria = Caused by ischemia Low cytosolic Ca²⁺ maintenance = Active transport mechanisms Calcium accumulation = Failure of ATP generation</p> Signup and view all the answers

    Match the following sources of cellular injury with their triggers:

    <p>Hypoxia = Reduced oxygen supply Ischemia = Lack of blood flow Exposure to toxins = Chemical reactions leading to Ca²⁺ disturbance Elevated Ca²⁺ = Activation of proteases and endonucleases</p> Signup and view all the answers

    Match the following cellular processes with their associated calcium roles:

    <p>Apoptosis = Triggered by excessive Ca²⁺ in certain conditions Cell signaling = Regulated by low cytosolic Ca²⁺ ATP generation = Compromised by mitochondrial damage due to Ca²⁺ Vesicle trafficking = Involves Ca²⁺ as a second messenger</p> Signup and view all the answers

    Match the following types of cellular responses to increased ROS levels:

    <p>Cellular aging = Long-term ROS exposure effects Apoptosis = Triggered by high ROS levels Signaling functions = Beneficial interactions with low ROS DNA repair mechanisms = Activated in response to DNA adducts</p> Signup and view all the answers

    Match the following mechanisms of free radical production with their descriptions:

    <p>Inflammation = Production of ROS by leukocytes via NADPH oxidase Enzymatic Metabolism = Conversion of chemicals into free radicals Transition Metals = Catalysis of free radicals through reactions involving iron Nitric Oxide (NO) = A free radical that can form reactive species like peroxynitrite</p> Signup and view all the answers

    Match the methods of free radical removal with their corresponding actions:

    <p>Spontaneous Decay = Inherent instability leading to decay of free radicals Antioxidants = Neutralization of free radicals by scavenging Metal Binding Proteins = Sequestration of metals to inhibit free radical reactions Enzymatic Defense Mechanisms = Decomposition of peroxides by specific enzymes</p> Signup and view all the answers

    Match the pathological effects of free radicals to their descriptions:

    <p>Lipid Peroxidation = Attack on unsaturated fatty acids in membranes Oxidative Modification of Proteins = Damage through oxidation of amino acid side chains Mitochondrial Dysfunction = Disruption caused by oxidative stress to cellular respiration Gene Mutations = Alterations in DNA due to oxidative damage</p> Signup and view all the answers

    Match the following enzymes to their specific function in oxidative defense:

    <p>Catalase = Decomposes hydrogen peroxide into water and oxygen Superoxide Dismutases (SODs) = Converts superoxide radicals into hydrogen peroxide and oxygen Glutathione Peroxidase = Reduces hydrogen peroxide and other peroxides Thioredoxin = Aids in the reduction of oxidized proteins</p> Signup and view all the answers

    Match the sources of free radicals with their specific characteristics:

    <p>NADPH Oxidase = Enzyme primarily producing ROS in leukocytes Iron = Metal that catalyzes free radical formation via Fenton reaction Carbon Tetrachloride (CCl₄) = Chemical converted into free radicals during metabolism Ozone (O₃) = Oxidizing agent that can generate free radicals</p> Signup and view all the answers

    Match the type of oxidative damage to its specific effect:

    <p>Lipid Peroxidation = Compromises the integrity of cellular membranes Protein Oxidation = Inactivates enzymes and disrupts structural proteins DNA Damage = Causes mutations due to oxidative changes in genetic material Cellular Signaling Disruption = Affects pathways involved in programmed cell death</p> Signup and view all the answers

    Match the types of antioxidants with their roles in cellular defense:

    <p>Vitamin E = Lipid-soluble antioxidant that protects cell membranes Ascorbic Acid = Water-soluble antioxidant effective in scavenging ROS Glutathione = Tripeptide antioxidant that detoxifies free radicals Flavonoids = Plant antioxidants known for neutralizing oxidative stress</p> Signup and view all the answers

    Match the following statements about free radicals to their truth:

    <p>Free radicals cause lipid peroxidation. = True: ROS can attack and damage membranes. Superoxide dismutase creates hydrogen peroxide. = True: SOD converts superoxide to H₂O₂. Catalase increases free radicals levels. = False: Catalase reduces H₂O₂ levels. Antioxidants amplify oxidative stress. = False: Antioxidants reduce the damage caused by free radicals.</p> Signup and view all the answers

    Match the following enzymes with their effects on cellular injury:

    <p>Phospholipases = Breakdown of membrane phospholipids leading to increased permeability Proteases = Degradation of cytoskeletal and membrane proteins Endonucleases = Fragmentation of DNA and chromatin ATPases = Increased consumption of ATP leading to energy depletion</p> Signup and view all the answers

    Match the terms with their correct descriptions:

    <p>Hypoxia = Maintained blood flow with limited oxygen Ischemia = Absence of blood flow preventing metabolism HIF-1 = Factor promoting angiogenesis and glycolysis during hypoxia ATP depletion = Initial cause of reversible cell injury leading to swelling</p> Signup and view all the answers

    Match the following events with their sequence during ischemic cell injury:

    <p>Oxygen deprivation = Cease of oxidative phosphorylation and ATP production ATP depletion = Leads to reversible cell injury Prolonged ischemia = Results in irreversible injury and cell death Neuronal damage = Can occur rapidly in severe ischemia</p> Signup and view all the answers

    Match the following cellular responses with their corresponding conditions:

    <p>Increased Ca²⁺ levels = Activates proteases and endonucleases Hypoxia = Allows for some anaerobic metabolism Ischemia = Cuts off blood supply entirely HIF-1 activation = Stimulates survival pathways under low oxygen</p> Signup and view all the answers

    Match the following diseases or conditions with their primary mechanism:

    <p>Hypoxia = Decreased oxygen supply Ischemia = Reduced blood flow Necrosis = Cell death due to sustained injury Apoptosis = Programmed cell death in response to stimuli</p> Signup and view all the answers

    Match the following cellular processes with their consequences:

    <p>Activation of ATPases = Leads to rapid ATP depletion Calcium homeostasis disruption = Exacerbates cell injury Endonuclease activity = Leads to potential DNA damage Excessive protease activation = Compromises structural integrity of cells</p> Signup and view all the answers

    Match the stages of ischemic cell injury with their outcomes:

    <p>Early ischemia = Cell and organelle swelling Continued ATP depletion = Reversible cell injury Irreversible damage = Progresses to necrosis HIF-1 response = Promotes adaptation to low oxygen</p> Signup and view all the answers

    Match the following definitions with terms:

    <p>Hypoxia = Inadequate oxygen supply despite blood flow Ischemia = Loss of blood supply leading to tissue injury Reactive oxygen species = Molecules that can damage cellular components Calcium overload = Causes malfunction in cellular signaling and injury</p> Signup and view all the answers

    Match the following types of injuries with their descriptions:

    <p>Therapeutic Hypothermia = Lowering body temperature to minimize cell injury Reperfusion Injury = Damage due to restored blood flow to ischemic tissue Intracellular Calcium Overload = Exacerbated calcium influx during reperfusion Inflammatory Response = Cytokine secretion and immune activation during ischemia</p> Signup and view all the answers

    Match the following mechanisms of reperfusion injury with their effects:

    <p>Oxidative Stress = Production of reactive oxygen species from reoxygenation Calcium Influx = Opening of mitochondrial permeability transition pore Cytokine Secretion = Attraction of neutrophils to reperfused areas Complement Activation = Exacerbation of cell injury through immune response</p> Signup and view all the answers

    Match the following terms related to ischemia with their implications:

    <p>Oxygen deprivation = Inadequate blood supply to tissues Metabolic demand reduction = Effect of hypothermia in ischemic injury Free radical generation = Consequences of oxidative stress upon reperfusion Calcium signaling = Critical factor affected during ischemic injury</p> Signup and view all the answers

    Match the following cellular responses to the stimuli during ischemia:

    <p>ATP depletion = Immediate injury consequence from hypoxia Increased inflammation = Triggered by danger signals from dead cells Neutrophil recruitment = Result of cytokine release during ischemia Mitochondrial damage = Caused by intracellular calcium overload</p> Signup and view all the answers

    Match the following specific types of reperfusion injuries with their causes:

    <p>Oxidative Damage = Reoxygenation generates reactive species Calcium Overload = Reperfusion leads to excess calcium influx Inflammation = Cytokine release attracts immune cells Complement Activation = IgM antibodies in ischemic tissues bind with proteins</p> Signup and view all the answers

    Match the following effects of therapeutic hypothermia with their mechanisms:

    <p>Reduced metabolic demand = Lowers energy consumption of cells Decreased swelling = Minimizes tissue injury Suppressed free radical formation = Prevents oxidative stress Inhibition of inflammation = Reduces immune cell activation</p> Signup and view all the answers

    Match the following substances associated with reperfusion injury to their roles:

    <p>Reactive oxygen species = Cause oxidative damage during reperfusion Cytokines = Signal for inflammation and immune response Calcium = Mediates mitochondrial injury Complement proteins = Amplify inflammatory responses and cell injury</p> Signup and view all the answers

    Match the following impacts of chemical (toxic) injury on the liver:

    <p>Drug metabolism = Primary function affected by chemical toxicity Cellular damage = Outcome of toxic substance exposure Inflammatory response = Can be triggered by toxic injuries Liver failure = Severe consequence of chemical injury over time</p> Signup and view all the answers

    Study Notes

    DNA Repair Mechanisms

    • DNA repair is activated during cell cycle arrest to correct damage using mechanisms like nucleotide excision repair, base excision repair, and double-strand break repair.
    • Successful repair allows cells to resume normal function and continue through the cell cycle.
    • If DNA damage is extensive and irreparable, the p53 protein initiates apoptosis via the mitochondrial pathway, preventing the proliferation of potentially oncogenic cells.
    • p53 plays a crucial role in cancer prevention by ensuring that cells with significant DNA damage do not survive.
    • Mutations in the p53 gene impair its ability to arrest the cell cycle or induce apoptosis, allowing damaged cells to evade death and potentially lead to tumor formation.

    Oxidative Stress and Free Radicals

    • Free radicals, particularly reactive oxygen species (ROS), are involved in cell injury across various conditions, including chemical and radiation injury.

    • ROS can attack and modify essential biomolecules, leading to cellular dysfunction.

    • Free radicals are generated through:

      • Normal metabolic processes, producing intermediates like superoxide anion and hydrogen peroxide.
      • Radiant energy, which hydrolyzes water into free radicals.
      • Inflammation, where leukocytes produce ROS.
      • Enzymatic metabolism of certain chemicals.
      • Transition metals that catalyze free radical reactions.

    • Free radicals can be removed via:

      • Spontaneous decay, where they can dismutate into stable forms.
      • Antioxidants, such as vitamins E and C, which neutralize free radicals.
      • Metal-binding proteins that sequester iron and copper.
      • Enzymatic mechanisms, including catalase and superoxide dismutases (SODs), which mitigate oxidative damage.

    • Pathological effects of ROS include:

      • Lipid peroxidation, compromising cell membrane integrity.
      • Oxidative modification of proteins, leading to enzyme inactivation and protein degradation.
      • DNA damage resulting in mutations and potential cancer development.

    Calcium Homeostasis in Cell Injury

    • Calcium ions (Ca²⁺) function as critical second messengers in various cellular activities but can cause cell injury when levels become excessively elevated.
    • Normal conditions maintain low cytosolic Ca²⁺ levels (~0.1 µmol) compared to extracellular levels (~1.3 mmol).
    • Calcium disturbance can occur due to ischemia or toxins, leading to Ca²⁺ influx and release from intracellular stores.
    • Excessive Ca²⁺ stimulates:
      • Mitochondrial damage, impairing ATP production.
      • Enzyme activation that damages membranes and cytoskeletal integrity.

    Hypoxia, Ischemia, and Reperfusion Injury

    • Ischemia results from reduced blood flow, often due to arterial obstruction, leading to severe tissue injury.

    • Hypoxia involves low oxygen supply but maintained blood flow, enabling some anaerobic metabolism.

    • Cellular response to hypoxia involves activating hypoxia-inducible factor-1 (HIF-1), enhancing survival pathways and angiogenesis.

    • Therapeutic hypothermia can reduce metabolic demand during ischemic injury.

    • Reperfusion injury occurs upon restoring blood flow to ischemic tissues and can induce:

      • Oxidative stress from free radical generation during reoxygenation.
      • Calcium overload exacerbated by influx during reperfusion, leading to further cell injury.
      • Inflammatory responses attracting neutrophils, causing additional tissue damage.
      • Complement system activation, worsening cell injury and inflammation.

    Chemical (Toxic) Injury

    • Chemical injuries significantly impact clinical medicine, particularly affecting the liver due to its role in drug metabolism.

    DNA Repair Mechanisms

    • During cell cycle arrest, DNA repair mechanisms such as nucleotide excision repair, base excision repair, and double-strand break repair are activated to correct DNA damage.
    • Successful DNA repair allows the cell to proceed through the cell cycle and maintain normal function.

    Outcome of Failed DNA Repair

    • When DNA damage is extensive and irreparable, the p53 protein triggers apoptosis via the mitochondrial pathway, preventing cell proliferation with oncogenic mutations.
    • p53 plays a crucial role in cancer prevention by eliminating damaged cells and reducing the risk of malignant transformation.

    Cancer and p53 Mutations

    • Mutations in the p53 gene impair its function in cell cycle arrest and apoptosis.
    • These mutations are often found in various cancers, allowing damaged cells to evade programmed death and continue dividing, which can lead to tumor formation.

    Oxidative Stress and Accumulation of Oxygen-Derived Free Radicals

    • Free radicals, particularly reactive oxygen species (ROS), are significant contributors to cell injury in conditions such as chemical exposure, radiation exposure, and ischemia-reperfusion injury.
    • Free radicals are highly reactive molecules with unpaired electrons, capable of damaging proteins, lipids, carbohydrates, and nucleic acids.

    Generation of Free Radicals

    • Free radicals are produced through normal metabolic processes including oxidative phosphorylation, inflammation, exposure to radiant energy like UV light, and enzymatic metabolism of certain chemicals.
    • Transition metals and nitric oxide can also contribute to free radical formation, leading to cellular damage.

    Removal of Free Radicals

    • Natural processes like spontaneous decay and the action of antioxidants (e.g., vitamins E and C, glutathione) help neutralize free radicals.
    • Metal-binding proteins sequester iron and copper to prevent harmful reactions, while enzymatic defense mechanisms include catalase, superoxide dismutases, and glutathione peroxidase, all of which mitigate oxidative damage.

    Pathological Effects of Free Radicals

    • Lipid peroxidation damages cell membranes, leading to compromised integrity and cellular dysfunction.
    • Free radicals can oxidize proteins, leading to enzyme inactivation and damage to structural proteins which escalate cellular degeneration.
    • Increased intracellular calcium activates enzymes like phospholipases, proteases, and endonucleases, resulting in further cellular injury and energy depletion.

    Hypoxia, Ischemia, and Reperfusion Injury

    • Ischemia, often resulting from blood flow obstruction, causes more severe cell injury than hypoxia, which involves reduced oxygen supply with maintained blood flow.
    • In hypoxia, cells can still produce energy via anaerobic glycolysis, while ischemia halts both aerobic and anaerobic metabolism, leading to rapid cell death.

    Mechanisms of Ischemic Cell Injury

    • Oxygen deprivation in ischemia leads to decreased ATP production, causing reversible cell injury that can progress to irreversible damage if ischemia persists.
    • Activation of hypoxia-inducible factor-1 (HIF-1) promotes adaptive responses such as angiogenesis and glycolysis, though effective therapies for ischemic injury remain under investigation.

    Reperfusion Injury

    • Reperfusion can paradoxically cause further tissue damage by generating free radicals upon reoxygenation and increasing intracellular calcium levels.
    • An inflammatory response during reperfusion exacerbates cellular injury by attracting immune cells and activating the complement system, leading to additional damage.

    Chemical (Toxic) Injury

    • Chemical injuries, particularly in the liver, restrict drug therapy and are caused by direct toxicity or conversion to toxic metabolites.
    • Direct toxicity arises when chemicals immediately damage cellular components, exemplified by mercuric chloride and cyanide poisoning.

    Conversion to Toxic Metabolites

    • Chemicals may become harmful after being metabolized into reactive forms, such as carbon tetrachloride and acetaminophen, primarily through the cytochrome P-450 enzyme system in the liver.

    Reversible Cell Injury

    • Reversible cell injury occurs through functional and structural changes that can be corrected by removing the harmful stimulus.
    • Cellular swelling is the most common early sign, resulting from disrupted ion and fluid balance within cells, potentially leading to organ swelling if widespread.

    DNA Repair Mechanisms

    • DNA repair is activated during cell cycle arrest to correct damage using mechanisms like nucleotide excision repair, base excision repair, and double-strand break repair.
    • Successful repair allows cells to resume normal function and continue through the cell cycle.
    • If DNA damage is extensive and irreparable, the p53 protein initiates apoptosis via the mitochondrial pathway, preventing the proliferation of potentially oncogenic cells.
    • p53 plays a crucial role in cancer prevention by ensuring that cells with significant DNA damage do not survive.
    • Mutations in the p53 gene impair its ability to arrest the cell cycle or induce apoptosis, allowing damaged cells to evade death and potentially lead to tumor formation.

    Oxidative Stress and Free Radicals

    • Free radicals, particularly reactive oxygen species (ROS), are involved in cell injury across various conditions, including chemical and radiation injury.

    • ROS can attack and modify essential biomolecules, leading to cellular dysfunction.

    • Free radicals are generated through:

      • Normal metabolic processes, producing intermediates like superoxide anion and hydrogen peroxide.
      • Radiant energy, which hydrolyzes water into free radicals.
      • Inflammation, where leukocytes produce ROS.
      • Enzymatic metabolism of certain chemicals.
      • Transition metals that catalyze free radical reactions.

    • Free radicals can be removed via:

      • Spontaneous decay, where they can dismutate into stable forms.
      • Antioxidants, such as vitamins E and C, which neutralize free radicals.
      • Metal-binding proteins that sequester iron and copper.
      • Enzymatic mechanisms, including catalase and superoxide dismutases (SODs), which mitigate oxidative damage.

    • Pathological effects of ROS include:

      • Lipid peroxidation, compromising cell membrane integrity.
      • Oxidative modification of proteins, leading to enzyme inactivation and protein degradation.
      • DNA damage resulting in mutations and potential cancer development.

    Calcium Homeostasis in Cell Injury

    • Calcium ions (Ca²⁺) function as critical second messengers in various cellular activities but can cause cell injury when levels become excessively elevated.
    • Normal conditions maintain low cytosolic Ca²⁺ levels (~0.1 µmol) compared to extracellular levels (~1.3 mmol).
    • Calcium disturbance can occur due to ischemia or toxins, leading to Ca²⁺ influx and release from intracellular stores.
    • Excessive Ca²⁺ stimulates:
      • Mitochondrial damage, impairing ATP production.
      • Enzyme activation that damages membranes and cytoskeletal integrity.

    Hypoxia, Ischemia, and Reperfusion Injury

    • Ischemia results from reduced blood flow, often due to arterial obstruction, leading to severe tissue injury.

    • Hypoxia involves low oxygen supply but maintained blood flow, enabling some anaerobic metabolism.

    • Cellular response to hypoxia involves activating hypoxia-inducible factor-1 (HIF-1), enhancing survival pathways and angiogenesis.

    • Therapeutic hypothermia can reduce metabolic demand during ischemic injury.

    • Reperfusion injury occurs upon restoring blood flow to ischemic tissues and can induce:

      • Oxidative stress from free radical generation during reoxygenation.
      • Calcium overload exacerbated by influx during reperfusion, leading to further cell injury.
      • Inflammatory responses attracting neutrophils, causing additional tissue damage.
      • Complement system activation, worsening cell injury and inflammation.

    Chemical (Toxic) Injury

    • Chemical injuries significantly impact clinical medicine, particularly affecting the liver due to its role in drug metabolism.

    Inflammation and Free Radicals

    • Activated leukocytes, including neutrophils and macrophages, generate reactive oxygen species (ROS) via NADPH oxidase during inflammation.
    • Certain exogenous chemicals, such as carbon tetrachloride (CCl₄), can be metabolized into free radicals (e.g., CCl₃).
    • Transition metals like iron and copper facilitate free radical formation through reactions such as the Fenton reaction, converting H₂O₂ into hydroxyl radicals (OH).
    • Nitric oxide (NO) acts as a free radical and can generate reactive species like the peroxynitrite anion (ONOO⁻).

    Removal of Free Radicals

    • Free radicals are unstable and can decay spontaneously; for example, superoxide (O₂⁻) dismutates into oxygen (O₂) and hydrogen peroxide (H₂O₂).
    • Antioxidants like vitamins E and A, ascorbic acid, and glutathione neutralize free radicals by scavenging them or preventing their formation.
    • Proteins such as transferrin, ferritin, lactoferrin, and ceruloplasmin bind iron and copper, reducing their potential to catalyze free radical reactions.

    Enzymatic Defense Mechanisms

    • Catalase decomposes hydrogen peroxide (H₂O₂) into water and oxygen, protecting cells from oxidative stress.
    • Superoxide dismutases (SODs) convert superoxide radicals (O₂⁻) into H₂O₂ and oxygen, located in various cellular compartments.
    • Glutathione peroxidase reduces H₂O₂ and other peroxides, safeguarding cells from oxidative damage.

    Pathological Effects of Free Radicals

    • Lipid peroxidation occurs when ROS attack unsaturated fatty acids in cell membranes, compromising membrane integrity and function.
    • Free radicals can oxidize proteins, disrupting enzyme activity and leading to cellular degradation.
    • DNA damage includes single and double-strand breaks, impacting cellular aging and cancer development.

    Calcium Homeostasis and Cell Injury

    • Calcium ions (Ca²⁺) act as essential second messengers in processes like muscle contraction and neurotransmitter release.
    • Normal cytosolic Ca²⁺ concentration remains low (~0.1 μmol), while extracellular levels are significantly higher (~1.3 mmol).
    • Ischemia and toxins can elevate cytosolic Ca²⁺, first by releasing Ca²⁺ from stores and later increasing influx due to damaged membrane channels.

    Mechanisms of Calcium-Induced Cell Injury

    • Mitochondrial permeability transition pore formation from excessive Ca²⁺ accumulation disrupts ATP generation, vital for survival.
    • Elevated Ca²⁺ activates enzymes such as phospholipases, proteases, and endonucleases, leading to membrane damage and DNA fragmentation.
    • Increased ATPase activity accelerates ATP depletion, hastening cell death.

    Hypoxia and Ischemia

    • Ischemia, characterized by reduced blood flow, leads to more severe injury than hypoxia, where blood flow is maintained but oxygen is limited.
    • In hypoxia, anaerobic glycolysis can persist; in ischemia, both aerobic and anaerobic metabolism cease, causing rapid cell injury.

    Mechanisms of Ischemic Cell Injury

    • Oxygen deprivation halts oxidative phosphorylation, leading to ATP depletion and reversible injury, which may progress to irreversible necrosis.
    • Hypoxia-Inducible Factor-1 (HIF-1) activation facilitates adaptation to low oxygen, promoting angiogenesis and glycolysis.
    • Therapeutic hypothermia reduces metabolic demands, swelling, and free radical formation, protecting cells during ischemic events.

    Reperfusion Injury

    • Reperfusion can paradoxically cause further damage through oxidative stress, intracellular calcium overload, inflammation, and complement system activation.
    • Reoxygenation leads to ROS production, overwhelming compromised antioxidant defenses.
    • Calcium influx during reperfusion exacerbates damage, while inflammation from released "danger signals" enhances injury.

    Chemical (Toxic) Injury

    • Chemical injuries, especially to the liver, limit drug therapy options and may result in liver damage.
    • Chemicals can cause direct toxicity by damaging cellular components or become toxic metabolites via cytochrome P-450 enzymatic conversion.

    Reversible Cell Injury

    • Reversible cell injury reflects functional and structural changes that can be corrected upon removing harmful stimuli.
    • Cellular swelling is often the first sign, associated with disrupted ion and fluid balance, leading to water accumulation and potential organ enlargement.

    DNA Repair Mechanisms

    • DNA repair is activated during cell cycle arrest to correct damage using mechanisms like nucleotide excision repair, base excision repair, and double-strand break repair.
    • Successful repair allows cells to resume normal function and continue through the cell cycle.
    • If DNA damage is extensive and irreparable, the p53 protein initiates apoptosis via the mitochondrial pathway, preventing the proliferation of potentially oncogenic cells.
    • p53 plays a crucial role in cancer prevention by ensuring that cells with significant DNA damage do not survive.
    • Mutations in the p53 gene impair its ability to arrest the cell cycle or induce apoptosis, allowing damaged cells to evade death and potentially lead to tumor formation.

    Oxidative Stress and Free Radicals

    • Free radicals, particularly reactive oxygen species (ROS), are involved in cell injury across various conditions, including chemical and radiation injury.

    • ROS can attack and modify essential biomolecules, leading to cellular dysfunction.

    • Free radicals are generated through:

      • Normal metabolic processes, producing intermediates like superoxide anion and hydrogen peroxide.
      • Radiant energy, which hydrolyzes water into free radicals.
      • Inflammation, where leukocytes produce ROS.
      • Enzymatic metabolism of certain chemicals.
      • Transition metals that catalyze free radical reactions.

    • Free radicals can be removed via:

      • Spontaneous decay, where they can dismutate into stable forms.
      • Antioxidants, such as vitamins E and C, which neutralize free radicals.
      • Metal-binding proteins that sequester iron and copper.
      • Enzymatic mechanisms, including catalase and superoxide dismutases (SODs), which mitigate oxidative damage.

    • Pathological effects of ROS include:

      • Lipid peroxidation, compromising cell membrane integrity.
      • Oxidative modification of proteins, leading to enzyme inactivation and protein degradation.
      • DNA damage resulting in mutations and potential cancer development.

    Calcium Homeostasis in Cell Injury

    • Calcium ions (Ca²⁺) function as critical second messengers in various cellular activities but can cause cell injury when levels become excessively elevated.
    • Normal conditions maintain low cytosolic Ca²⁺ levels (~0.1 µmol) compared to extracellular levels (~1.3 mmol).
    • Calcium disturbance can occur due to ischemia or toxins, leading to Ca²⁺ influx and release from intracellular stores.
    • Excessive Ca²⁺ stimulates:
      • Mitochondrial damage, impairing ATP production.
      • Enzyme activation that damages membranes and cytoskeletal integrity.

    Hypoxia, Ischemia, and Reperfusion Injury

    • Ischemia results from reduced blood flow, often due to arterial obstruction, leading to severe tissue injury.

    • Hypoxia involves low oxygen supply but maintained blood flow, enabling some anaerobic metabolism.

    • Cellular response to hypoxia involves activating hypoxia-inducible factor-1 (HIF-1), enhancing survival pathways and angiogenesis.

    • Therapeutic hypothermia can reduce metabolic demand during ischemic injury.

    • Reperfusion injury occurs upon restoring blood flow to ischemic tissues and can induce:

      • Oxidative stress from free radical generation during reoxygenation.
      • Calcium overload exacerbated by influx during reperfusion, leading to further cell injury.
      • Inflammatory responses attracting neutrophils, causing additional tissue damage.
      • Complement system activation, worsening cell injury and inflammation.

    Chemical (Toxic) Injury

    • Chemical injuries significantly impact clinical medicine, particularly affecting the liver due to its role in drug metabolism.

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    Description

    Explore the intricate processes of DNA repair mechanisms and the impact of oxidative stress on cellular health. This quiz delves into how cells correct damage and the implications of p53 in cancer prevention, alongside the role of free radicals in cell injury. Test your knowledge on these critical biological concepts.

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