Study Guide 1 524

How is calcium [and phosphate] distributed in the body?

· 99% of calcium Is part of bone · 1% of calcium is in blood as Free CA ions (45%), Bound to albumin (40%), Bound to anions (15%) · 80% of phosphate is in bone · Other is in high energy bond in ATP

Generally, know how the T tubule allows for the AP to lead to a muscle contraction

· Action potential activates voltage-gated L type calcium channels, causing small influx of calcium · Channels physically linked to RyR · Large amount of calcium is released from intracellular storage via RYR muscle contraction

Understand the action potential

· Action potential: short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls to send electrical signal STEPS 1. NA channels open, NA enters cells (Stimulus) 2. K channels open, K begins to leave cells (Depol) 3. NA channels become refractory so no more NA enters cell (Repol) 4. K channels close, Na channels reset (Hyperpol) 5. Extra K outside diffuses away (resting)

What is Alzheimer's disease and what causes is it

· Alzheimer's disease (AD): slowly progressive neurodivergent disorder involving cortical and hippocampal neuronal loss leading to impairment in cognition and profound memory loss. · Characterized by Accumulation of aggregated amyloid beta peptide (Aβ) and Excessively phosphorylated microtubule-associated protein tau (Forms NFTs) · Amyloid theory: links AD solely to formation, accumulation, and toxicities of Aβ peptides

What are antioxidants and how are they grouped?

· Biological definition: synthetic or natural substances that prevent or delay deterioration of a product, or are capable of counteracting the damaging effects of oxidation in animal tissues · Grouped by enzymatic or non-enzymatic

Describe when and how neural tube defects occur. What are the severities associated with each?

· Birth defects of the brain and spinal cord · Occurs when the neural tube doesn't close at a certain point on the tube (should close around 30th day of fertilization) · Can occur at various levels of the neural tube

Understand the proposed mechanic of action of calcitriol in moving calcium from the intestinal lumen to the blood

· Calcitriol activates is activated in the kidneys and sent to blood · Calcitriol gets imported into the cells (easily done because Vitamin D3 is lipid soluble and can cross the membrane). Vit D binds with VDR · Calcitriol/VDR complex translocates to nucleus and regulate the transcription of calbindin · Calbindin/calcium complex in cytoplasm moves through the cell to get close to calcium ATPase · ATPase frees calcium from calbindin to pump calcium into blood

Understand the reasoning behind excitation-contraction coupling.

· Controls the contraction (and relaxation) of skeletal or smooth muscle · Depends on the function of the intracellular Ca concentration · Definition: signal transduction mechanism by which extrinsic stimuli (electrical action potential) are then translated or converted to a mechanical response (muscle contraction) · Action potential is propagated by Na entry via voltage-gated Na+ channels, but ultimately the AP is converted to an elevation in Ca in the muscles (causes contraction to occur

1. How is folate involved in NTDs? What are current recommendations? Other considerations beyond dietary intake? Does folic acid supplementation help occurrence of NTDs, if so, how?

· Folic acid: water soluble vitamin B9, aka folate (Found in leafy green vegetables, fruits, dried beans, peas, nuts) · Low serum folate is correlated with NTDs -Supplement with 400-800 ug per day o Reduces risk of NTDs by 2/3-3/4 when supplemented -Because it's not all, clearly a sub-set of NTDs are not folate dependent. · Connection found using animal studies of aminopterin in 1949 -Aminopterin is an anti-metabolite of folic acid à will block action of folic acid and cause deficiencies. -Aminopterin on pregnant rats caused prenatal death but not malformations (A lesser deficiency of folic acid caused deficiencies, but a greater one impacted the embryo so much it caused death.) · 5,10-metylentetrahydrofolate reductase --> pathway for recycling folate · Homozygotes for particular variants are thought to be at risk for NTD and higher than normal supplementation has been recommended. · NTDs definitely helps the prevalence of NTDs --> decreased from 1.58 per 1,000 births before fortification to 0.86 per 1000 births during full fortification period (46% reduction)

Describe macular degeneration.

· Fovea and small surrounding area are destroyed. · Creates blind spot-on retina. · Most common in older individuals. · Two types (Wet causes vision loss due to abnormal blood vessel growth, Dry results from atrophy of the retinal pigment, causes vision loss through loss of photoreceptors.) -Can be age related -Causitive factor can be oxidative stress (AREds have been used to discover this)

1. Describe what happens to iron homeostasis in the ageing brain

· Increased concentration of iron with ageing caused by Increased blood-brain barrier permeability, Inflammation (caused by increased BBB permeability), Redistribution of iron within the brain (iron deposits move), Changes in iron homeostasis (free vs. bound) · Ageing compromises iron homeostatic system à iron is not efficiently chelated (bound) by storage proteins or other molecules Total iron concentration increases with age in selective brain regions. · Iron complexes accumulate in brain regions associated with motor and cognitive impairment · Alzheimer's and Parkinson's are results of altered cellular iron distribution and accumulation. · Advances in iron quantification techniques (MRIs) demonstrated that brain iron increases with aging · Decreased plasma iron in AD patients is caused by transferrin desaturation

Why are ion channels important and where

· Ion channels and transporters regulate membrane electrical potential and therefore cell excitability (allow for muscle contraction) · Action potentials are initiated and propagated by ions (Calcium and Potassium ions) Muscle contraction and relaxation are strictly calcium-dependent · Ion channels and transporters are among the most common therapeutic targets (heart, gut, kidney, brain, lung)

Describe cataracts and their development

· Leading cause of world-wide blindness. · Occurrence will increase with increase in aging population. · Develop as opaque regions of the lens either acutely, or as a result of general age damage. -Lens opacities means that light will be scattered which leads to blurred vision. · Caused by accumulated damage over time... -Risk factors include smoking, UV light, diabetes, micronutrient deficiencies (riboflavin, calcium, zing, selenium) and micronutrient toxicities (selenium)

Describe photoreception using light entering the eye and the various structures of the retina as descriptors of how photoreceptors are activated and the signal transmitted.

· Light enters the eye by passing through the iris and pupil and hits the retina · Retina contains cells that are sensitive to light (Rods and Cones) that are formed from the combination of retinal and opsin (a protein) · When light hits the retina, it moves retinal from cis to trans · Formation change sends an electrical signal to the brain via the optic nerve

Describe folate's use/role in methotrexate treatment of cancer

· Methotrexate is an anti-cancer drug that inhibits folic acid metabolism needed for DNA synthesis · Cancer cells are susceptible to deprivation of folic acid before normal cells due to their high rate of division ---> however needs to be selectively detrimental to neoplastic (cancer) cells. · Leucovorin --> reverses the actions of methotrexate at a specific time after methotrexate infusion (Referred to as leucovorin rescue) · Failure to stop methotrexate action can result in cytotoxic damage to all cells, not just cancer cells. · Monitor serum methotrexate to determine how much leucovorin is needed to counteract effects.

Understand the cyclical process of bone remodeling.

Composed of bone resorption and bone formation -Resorption (Osteoclasts remove a portion of the bone to be replaced later by osteoblasts, Vital step for signaling bone formation) -Formation (Osteoblasts lay down collagen and mineral deposits over the area previously remodeled by osteoclasts, Vital for maintaining bone mineral density and bone strength)

How are ion channels important in EC coupling and muscle contraction

Muscle membrane potential depends on... -Relative permeablility to potassium (K+ is the primary ion permeable at rest) -Na+/K+ ATPase pump (exchanges 3 intracellular Na+ for 2 extracellular K+ leaving a net negative intracellular charge, action is energy dependent) -Calcium-activated potassium channels (activated by elevated Ca_ in cytoplasm, may be more important during repolarization in muscle, i.e. voltage-gated K channels are key to repolarization or neurons following AP) Steps that relate to ion channels -Synaptic transmission -Action Potential -EC coupling

Know the different forms of retinoids and where there are found in the body and from dietary sources

- Retinal esters: Stable storage form of Vit A, Aldehyde form, Found in animals, Found in the eye to help with vision - Retinol: Found in animals, Alcohol form, Found in the body, is transported to the retina via circulation. - Retinoic acid: Acid form, Found in animals, Found in the skin/bone

CVD and antioxidants

-High dose vitamin supplementation increases heart disease risk -Fruit and vegetable intake protective -Inverse relationship with vitamin E consumption and coronary heart disease (consumption of supplemental doses increase risk) -Supplement scheduling of Vit C/E/beta carotene show mixed results and may depend on underlying risk of population

Info on RNS

-In the cytoplasm - Nitric oxide production from Arginine which functions - NO is important as a neurotransmitter, BP regulator, and cytotoxic agent - If there's a buildup of NO this can cause danger

Enzymatic antioxidants

-Enzymatic: endogenous controllers of free radical elimination -Have enzymes in the body to convert these substances to stable forms - Examples are SOD, catalase, glutathione perodixase - Important in elimination free radicals

What is the composition of bone?

-Inorganic (67%)= Hydroxyapatite (calcium, phosphate, and hydroxide) -Organic (33%)= Type 1 collagen, and non collagen strucutral proteins

Non-enzymatic antioxidants

-Non-enzymatic: role is influenced by feeding behavior and diet sufficiency -Examples are Minerals (Zinc, Selenium), Carotenoids (β-carotene, lycopene, lutein, zeaxanthin), Vitamins (A, C, E, K)

Describe the AREDS study as it relates to AMD

-Evaluates the effect of high-dose vitamin C and E, beta-carotene and zinc formulations on age-related macular degeneration (AMD) progression and visual acuity -Varied results: some have no impact on opacities (cataracts), potential protection in AMD progression -Many products on the market are result of this study -Overall results: micronutrients play a role as antioxidants in protection, but this is likely a very long term use effect, cannot be done by short term use

Formation ROS

- Primary source is from energy production as a natural byproduct of oxygen metabolism - Outside the body i. Environmental contaminants ii. Ionizing and UV radiation (something we are constantly exposed to) - Inside the body i. Prolonged low blood flow states (atherosclerosis, heart attacks, stroke) ii. Diet (fatty and processed foods) Low levels of antioxidants

Understand the biosynthesis of retinal/retinol from provitamins.

- Retinal and Retinol form from Provitamin form (Carotenoids): 1. Beta carotene is consumed via foods such as dark leafy greens, carrots, and orange-colored fruits. 2. B-carotene 15-15' monooxygenase is a enzyme that cleaves the carbon-carbon bond at center and splits Beta Carotene in two. Enzyme interacts with water to add carboxyl groups onto both ends of Beta Carotene and then splits the carotenoid symmetrically in 2. Enzyme requires vitamin E to work. 3. Split forms retinoids

Types of ROS

- Superoxide (O2-) i. Reduced molecular oxygen, precursor to other ROS. - Hydrogen peroxide i. Formed from the dismutation of superoxide. - Hydroxyl Radical (OH-) i. Product of Fenton reaction catalyzed by free Fe and Cu. - Singlet oxygen i. Oxygen at an excited state, requiring photosensitizers and photons ii. Plants form during photosynthesis Animals form during photoreception, retinal/retinol isomerization in vision

General info ROS

-AKA Free oxygen radicals -Any molecule with an unpaired electron (OH-, H2O2) -EXTREMELY chemically reactive -Cause damage to cell membranes which causes deterioration of cells -Responsible for roles in more than 100 human diseases (Cancer, heart attacks, stroke, arthritis) -Can be useful (i.e. can damage a tumor) or detrimental (i.e. can hurt normal human tissues)

How do osteoclasts resorb bone

-Attaches to bone surface via integrin-mediated binding to bone matrix bone proteins -When enough integrin binding has occurred the osteoclast is anchored and a sealed space is form -Ruffled boarder on osteoclast increases surface area -Acid is secreted in the sealed space forming an extracellular lysosome

Role of Osteoblasts

-Bone formation function -Synthesizes matrix proteins such as type 1 collagen, osteocalcin, and others -In charge of mineralization -Activates osteoclasts via RANKL -Have receptors for Parathyroid hormone, calcitonin, vitamin d, cytokines, and growth factors -Main product is collagen -When they become encased in bone, they become osteocytes

Role of osteoclasts

-Bone resorption functions -Dissolve bone -Made of large multinucleated giant cells -Resorb bone

Describe how certain polymorphisms in antioxidant enzymes can impact disease risk.

-Can cause favorable or negative impacts -mnSOD mutation (Highly penetrate polymorphism in mnSOD gene in human genome, Higher prostate breast cancer risk, higher cardiomyopathy risk) -Catalase mutation (higher breast cancer risk) -GPX-1 mutation (prevalent polymorphism PROTECTIVE against lung cancer in smokers)

Actions of PTH and what is it

-Parathyroid senses serum calcium levels and releases PTH if they become too low -PTH stimulated activity of 25-hydroxyvitamin D1-a-hydroxylase enzume in the kidney which results in calcitriol being formed (which is the biologically active version of vitamin D) -Increased amount of calcitriol restores calcium levels by Activating vitamin D dependent transport system in the small intestine which increases absorption of vitamin D, Increasing the reabsorption of calcium by the kidneys. Increasing mobilization of calcium from bone into circulation Overall actions... -Increases serum Ca -Decreases Pi (inorganic phosphate, increases from bone resorption, net loss overall due to kidney excretion) -Inhibits osteoblast function (Bone) -Acts on kidney to increase calcium resorption and phosphate excretion (Kidney, acts on distal tubules) as well as to stimulate vitamin D activation (calcidiol-calcitriol)

General mechanism through which enzymes/pathways defend against free radica;s

-Prevents the transfer of electron from O2 to organic molecules -Stabilizes free radicals -Terminates free radical reactions

Calcitonin definition and actions

-Produced in thyroid -Inhibits osteoclast mediated bone resorption -Promotes renal Ca excretion -Limited role

Cancer and relation between free radicals

-ROS and RNS involved in all of the hallmarks of tumorigenesis -Effects either protective (i.e. triggering apoptosis) or harmful (i.e. promoting cell division) -Complex relationship between cancer and antioxidants (Potential benefit of vitamin E, C, selenium, beta carotene on cancer, May interfere with efficacy of cancer treatment) -Selenium (Glutathione peroxidase supplementation shows decreased future cancer risk in those with history of squamous cell carcinoma, lower risk of total canacer) -Combo antioxidants (High risk patient population for GI cancers show No protective effect for Vitamin ACE combo on esophageal, gastric, colorectal, pancreatic, or liver cancer, Limited but positive potential for selenium on general GI cancer risk)

How/where is Vit D converted/activated?

-Skin (UV light converts 7-dehydrocholesterol in the skin to cholecalciferol, Pre-vitamin D is directly ingested) -Liver (Cholecalciferol is converted to calcidiol in the liver) -Kidney (Cholecalciferol is converted to calcidiol in the liver) -PTH (Parathormone (PTH) stimulates resorption of Ca and PO4)

What are the common types of neural tube defects and severities of each

-Spina Bifida (Less severe, "Split spine", Incomplete closure of the embryonic neural tube results in an incompletely formed spinal cord during the first month of pregnancy. Usually, nerve damage that causes at least some paralysis of the leg, will impact the lower end of the body.) -Anencephaly (More severe, Cranial end of the neural tube fails to close. Results in the absence of a major portion of the brain, skull, and scalp. Babies with anencephaly are either stillborn or die shortly after birth.)

describe the enzymes/pathways which defend against free radicals

-Superoxide dismutase (Eliminates superoxide produced from ETC in mitochondria, Produces hydrogen peroxide, MnSOD and Cu-Zn SOD) -Catalase (Eliminates hydrogen peroxide produced in peroxisome) -Glutathione peroxidase (Cytosolic enzyme, Eliminates hydrogen peroxide and some lipid peroxide, Requires reduced glutathione (GSH) as substrate) -NON-Enzyme (diet, supplementation)

Types of ion channels

-Voltage-gated Na channels (action potential propagation from neuron) -Voltage-dependent Ca channels (L and N type) -Voltage-gated K channels

Summary of Skeletal Muscle Contraction (describe the steps)

1. Neuronal action potential reaches nerve terminal 2. N-type voltage-gated Ca2+ channels activate by AP 3. Ca2+ entry triggers ACh secretion into synaptic cleft 4. ACh binds to nicotinic ACh receptor/channels at post-synaptic membrane, causing cation influx and depolarization 5. Depolarization of post-synapse triggers Na+ channgel activation and AP within muscle and down T tubules 6. AP activates voltage-gated L-type Ca2+ channels, causing small calcium influx 7. DHPR (L-type Ca2+ channels) are physically linked to RyR 8. Large amount of calcium is released from intracellular stores via RyR

Location of ROS and what occurs at each

i. Cell membrane (impacts cell integrity and protection) ii. Mitochondria - Converts energy for the cell by generating ATP via oxidative phosphorylation - If oxygen is prematurely and incompletely reduced in the ETC while forming ATP, it will form the superoxide radical which will leak out into the cytoplasm - Can lead to inactivation of specific enzymes or lipid peroxidation and in some cases destruction of the cell iii. Smooth ER - Detoxifies drugs and while so doing It leaks superoxide (similar to the mitochondria) iv. Peroxisomes - Contains oxidases for degradation of various substrates Requires O2 in order to degrade structures and as a byproduct it generates H2O2

Describe the events at the NMJ leading to propagation of the signal from the neuron to the muscle

· NMJ controls skeletal muscle movement through impulses from somatic motor neurons that are passed through the NMJ to the other side STEPS 1. Action potential activates voltage-gated calcium channels (N-type) in presynaptic membrane which causes... 2.Acetylcholine (Ach) containing vesicle fusion and Ach release 3.ACh binds to nicotinic ACh receptors/channels on post-synaptic membrane à NA+ influx depoloarizes membrane which spreads to adjacement membrane and activates Na+ channels 4.Local change in voltage at the NMJ due to influx of Na+ spreads along sarcolemma in a depolarizing wave Effects are rapid due to presence of acetylcholinesterases in the synaptic cleft

How is iron thought to impact neurodegeneration

· Neuronal iron accumulation induces damage by apoptosis: -Glial iron accumulation can induce an inflammatory state through release of pro-inflammatory cytokines and result in self-propelling cycle of neuroinflammation and neurodegeneration. · Iron in several proteins is involved in oxygen transport, oxidative phosphorylation, myelin production, and synthesis and metabolism of neurotransmitters. · Abnormal iron homeostasis can induce cellular damage through hydroxyl radical production, which can cause the oxidation and modification of lipids, proteins, carbs, and DNA. · Alzheimer's and Parkinson's result from iron accumulation in brain regions associated with iron distribution and accumulation. · Accumulation of iron can induce neurodegenerative processes through mechanisms involving Catecholamine classes of neurotransmitters (dopamine) oxidized to highly reactive or toxic structures via the reduction of ferric iron or enzymatically. - Ferric iron has bene shown to participate in neurotoxin generation related to Parkinson's. -Aggregation of proteins involved in neurodegenerative disorders (i.e. hyper-phosphorylated tau protein) have been shown to be triggered by ferric iron concentration. -Inclusion bodies containing damaged or aggregated proteins could cause endoplasmic reticulum stress. (Common feature of several neurodegenerative diseases. Iron toxicity through apoptosis and ferroptosis can occur.)

Role of antioxidants on cataracts

· Oxidative stress leads to lens damage: -Micronutrient deficiencies of riboflavin, selenium, and zinc can cause cataracts due to decreased function of oxidative stress proteins since these are cofactors. · Antioxidant carotenoids in the vitamin A family play a role -Lutein can be converted to zeaxanthin in the body and is radioprotective: (Lutein reduces blue light damage., Protects against peroxidation of fatty acids in the photoreceptor membrane and protects blood vessels supplying macular region.)

How does RANKL surface expression on osteoblasts influence osteoclasts?

· RANKLà Receptor activator of nuclear factor kappa-B ligand · PTH attaches to blast which causes blast to express RANKL on surface · RANKL attaches to RANK on osteoclast precursor cells which then causes the formation of osteoclasts

Describe Neurulation

· Refers to folding process in vertebrate embryos, which includes transformation of the neural plate into the neural tube · Necessary for CNS and PNS development · Occurs primarily during first trimester "critical periods"

What evidence is there that cataracts are influenced by nutrition?

· Risk factors for cataracts include micronutrient deficiencies and toxicities (see above) · Emory mouse showed that caloric restriction delays cataract onset time and improves blood glucose control where as hyperglycemia and diabetes causes significant oxidative stress.

Understand how dark adaptation is related to vitamin a status

· Rods detect low light (as low as one photon of light) whereas cones are less sensitive. · Bright light depletes rhodopsin (photobleaching) (rods are depleted, only cones are there). · Sudden shift from bright to dark makes it difficult to see because there aren't many rods present. · Rhodopsin is synthesized in a few minutes meaning vision becomes improved. Dark adaptation time=time required to synthesize new rhodopsin in the dark -Vit A plays role (dark time takes longer with vit A deficiency)

What is the relationship between iron and Tau?

· Tau: a neuronal microtubule stabilizing protein · Contributes to axonal transport, growth, and morphology. · Tau mis regulation and deposition correlated with neuronal cell death (Frontotemporal dementia and Parkinsonism. Alzheimer's neurofibrillary tangles are composed of phosphorylated Tau.) · Iron binds to tau and affects its phosphorylation and induces aggregation of hyperphosphorylated tau (can be reversed using iron chelators)

How is APP related to plaques and iron?

· Translation of the amyloid precursor protein (APP) is directly regulated by cellular iron level through mRNA modification of APP transcript · APP may produce Aβ when cleaved, but it's primary role is misunderstood

Understand and describe the visual cycle as it relates for Vitamin A movement into the eye, chemical conversion within the eye, and activation of retinal cells to send visual information to the brain

· Visual Cycle: a process by which light impacting on the retina of the eye is converted to an electrical signal. Relies heavily on Vitamin A metabolism. · Visual cycle occurs when Retinol forms Retinal. · Retinol moves to the retina via the circulation and is moved into retinal pigment epithelial cells where it's esterified and stored as retinyl esters · When needed, retinyl ester is broken apart (hydrolyzed) and isomerized into cis-retinol which can be formed into cis-retinal · In the retina, cis-retinal binds to opsin to make rhodopsin (in rods) and iodopsin (in cones) -Retinal isomerizes from cis to trans when light hits the eye -formation change sends signal to brain via optic nerve

What is apoE and how does it relate to AD

· apoE: apolipoprotein E allele, associated with very low-density lipoproteins and high-density lipoprotein, ·Strongest genetic risk factor for the development of AD · Its gene dosage effect on the age of onset of the disease has focused attention to importance of apoE in neurobiology and neurodegenerative disease. · Exists in three isoforms (E3 is most common) · Binds to specific cell-surface receptors including the LDL receptor--> homeostatic control of plasma and tissue lipid · Highly expressed in the brain and constitutes the principal lipid transport system in CSF (Plays crucial role in repair by redistributing lipids to regenerating axons and Schwann cells during remyelination) · apoE is primary expressed by astrocytes with lower expression in microglia