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115 Cards in this Set
- Front
- Back
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What was used as the end point in the Experiment Design Study that was a good indicator of tumors?
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GST-P Foci
-Was used instead of tumors because of the long latency period for tumors to grow -Can use a dye in the liver to show if this is present -Creates precancerous lesions -If found in the liver then there is damage or mutation (should be in the placenta) *Similar to Barret's Esophagus and metaplasia |
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Who limits the amount of Aflatoxin B1 in foods?
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-FDA
*If the #'s exceed the guidelines then the food is considered adulterated |
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Aflatoxin B1
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A microtoxin produced by molds
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What is the cancer causing form of colon cancer in rats?
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Methylazoxymethane
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What are performed on mold toxins?
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Risk assessment tests to determine what is an acceptable level of risk exposure if found in a food
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What would be a safe level or considered a zero risk for mold toxins to be in a food?
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1 cancer over a million people over a lifetime
*This number usually greatly overestimates the risk of the toxins |
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What is a Phase II metabolism drug?
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UDP-Glucuronosyl transferase
(Ex: Adds a glucorinde group onto methylazoxymethane to be excreted into the urine) |
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What effects did Indole-3-Carbinol have in the Experimental Design study
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-Acted as a tumor promoter
-Was given to the rats after they had already been affected by the carcinogen *Would've promoted Phase I and II metabolism if given with the chemicals |
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What is a Mercapturic acid?
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-Formed by Glutathione S-Transferase reacting with substances formed from Phase II metabolism
-Can be readily excreted in the urine -N-acetylated cysteine residue |
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Where can glucoronide left over from Phase II metabolism of methylazoxymethane go?
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-To the bile (Bile is made in the liver and so is the glucoronide)
-The bile goes thru to the colon -A rat's colon has beta-glucoronidase which cleaves off the beta-glucoronide -Left in the colon is the methylazoxymethane which causes cancer |
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Which are the animals which are unable to synthesize ascorbic acid?
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-Humans
-Some primates -Guinea pigs -Some birds -Some fish |
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What is the enzyme that some animals lack to convert glucose to ascorbic acid in the body?
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Gulonolactone oxidase
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How does ascorbic acid become oxidized?
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-Ascorbic acid starts in the reduced form (due to H's present on the O's)
-It is then converted into semidehydroascorbic acid radical (free radical but not dangerous or unstable) because it donates a protein to either Fe or Cu -The intermediate is then further oxidized to form Dehydroascorbic acid |
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How can the oxidized form of ascorbic acid (dehydroascorbic acid) be reduced?
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-Dehydroascorbic acid can be reduced by the enzyme dehydroascorbic acid reductase
***For the reduction reaction the occur, a reducing agent is needed (reduced glutathione) -2GSH is coupled with the reduction reaction to form GSSG (oxidized glutathione) so that dehydroascorbic acid can be reduced to ascorbic acid |
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What forms can the kidney excrete vitamin C efficiently?
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-Dehyrdroascorbic acid
-2,3-diketogulonic acid ***can not recover vitamin C from this form |
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What is Oxalic acid and its effects?
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-Break down product of 2,3-diketogulonic acid that is excreted in the urine from people taking megadoses of vitamin C
-Production of this may react with calcium and may make people more prone to kidney stones |
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What is the most "powerful" antioxidant?
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Vitamin C
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What other antioxidants can vitamin C regenerate?
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-Vit. E
-Glutathione -Uric Acid |
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What can be used to show if there is a vitamin C deficiency and how does vitamin C work in this aspect?
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-By seeing if proline and lysine have been hydroxylated
-Vitamin C works with the finished proteins (post-translational) by keeping the Fe in the reduced form in the hydroxylases so they function properly -alpha-ketoglutarate is needed for the reaction to work as well (this is essential for structural proteins such as collagen) |
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What is the Fenton Reaction?
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Fe (2+) + H2O2 ---> Fe (3+) + OH- + OH*
-(OH*) = hydroxy free radical which is very dangerous to cells -Ascorbic acid can accelerate this reaction |
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Which form of Fe is not mostly found in the body?
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-Fe (+2) = free Fe
***Storage or metabolism problems can increase the amount of free Fe in the body |
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What was the 1st study on Vitamin C?
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-Looked at the average # of colds, # of sick days, and average severity of colds
***no difference in numbers ***all different studies were used which were not pooled together |
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What was the 2nd study on Vitamin C?
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-Metanalysis was used = Uses past studies combined together to view a trend which meet a statistical criteria
-Large sample size (n) to avoid type 2 error (what happens when there is thought to be a difference between two groups when there isn't) -Relative risk of getting a cold by taking vitamin C = no effect -Relative effect on duration of a cold = small effect -When someone is stressed with a cold and they take vitamin C = small change |
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What is the term used that relates to the probability of avoiding a type 2 error?
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-Power
***Lower type 2 error = more power |
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Where can nitrosamines form?
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-In vivo
-In foods -In the environment *All scenarios depend on the environment *nitrosamines are stable in the environment (need phase I metabolism to be cancer causing) |
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What is a toxic metabolite?
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Nitrite
*Can prevent the growth of clostridium botulinum (grows above 4.6 and needs an anaerobic environment) |
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How do nitrosamines form?
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Nitrate (used in higher amounts under strict regulation)--->Nitrite<--->Nitrous acid<--->Nitrous anhydride--->Dimethyl amine --->Dimethylnitrosamine (Volatile and can vaporize)
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What is considered a nitrousating agent?
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-Nitrous anhydride
*Can react with amines to form dimethylnitrosamine |
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What can nitrates bind to?
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Hemoglobin compounds causing hemoglobin malfunction
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What reaction can ascorbic acid block?
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Nitrite to Nitrous acid
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What reaction is accelerated by an acidic environment (low pH) during nitrosamine formation?
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Dimethyl amine to dimethylnitrosamine
***This reaction is also accelerated by heat and when amines are present |
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Where would nitrosamines be formed in the body?
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In the stomach because nitrites like acidic environments
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What can double the risk of colorectal cancer?
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Increase of nitrosamines
*heating u foods can kill the toxin (Ex: cooking canned soup) and refrigeration |
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What is DMT-1's function?
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-Brings the non-heme form of Fe found in plants into the enterocyte
-Can carry Fe out of the endocytized vesicle containing transferrin -Can fuse to ferroportin to the basolateral side of the membrane |
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What is heme oxygenase's function?
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Catalyzes the hydrolysis of Fe that releases it from the heme
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What happens to a non-heme Fe when bound to a chelator?
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An insoluble complex is formed and the Fe is excreted in the feces
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What is HCP-1's function?
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Transports heme containing Fe into the enterocyte
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What is the function of ferritin?
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-The complex can be stored as ferric oxide hydroxy crystals
-Can cause inflammation if plasma levels (indicators if Fe status) are increased and can result in anemia -Responds to inflammatory processes (acute phase reactant protein) -Not stable and release Fe when necessary (requires Niacin riboflavin or vit. C) **When drained of Fe = Apoferritin |
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What is the function of ferroportin?
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-Forms a vesicle at the basolateral side
-Only known transporter to export Fe out of the enterocyte -Binds Fe to transferrin -Degraded by hepicidin -Decrease of this causes an increase of Fe within the cells |
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What is mobilferin's function?
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-Part of the chaperone complex to the basolateral side with the beta-integrin protein
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What is ceruloplasmin's function?
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-Enzyme that oxidizes Fe after exported out of the liver cells
-Does not release Fe from mucosa |
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What is Hephaestin's function?
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-Oxidizes Fe after leaving the intestinal enterocyte (converts ferrous to ferric form)
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What must be present to bind Fe to transferrin?
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HCO3
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What is Transferrin's function?
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-Binds to the ferric form
-Produced in the liver -Post translational modification of the C in CHO and N in the protein |
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What is the function of hepcidin?
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-Peptide hormone
-Deficiency causesincrease of Fe in the blood causing Hemochromatosis -Increase causes anemia ***Most important for Fe homeostasis -Inhibits Fe release from intestinal cells -Binds to ferroportin -Made by hepatocytes |
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What is the function of Transferrin Receptor 1 (TFR-1)?
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-Increase of Fe in the cells decreases this gene expression (negative modulation)
-Bind to clathrin coated pits along with the DMT-1 receptors |
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What causes Fe to dissociate from the transferrin containing vesicle?
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A drop in the pH
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What is clathrin?
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-A protein that coats endocytotic cells
-Creates pits to form vesicles to attract the Fe complex (where the pH drops and Fe dissociates from transferrin) then clathrin migrates back to the cell surface |
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What happen if nitrite is found to cause cancer?
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-It is considered a food additive and has to be banned
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What was thought as an alternative to using nitrites?
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Irridation
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How would a plant form cholesterol?
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-Ergosterol (plant sterol) to ergocalciferol (Vit. D2)
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How is cholesterol formed in the skin?
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-Cholesterol to dehydrocholesterol (Has an added double bond) in the skin
-Dehydrocholesterol oxidizes to form 7 Dehydrocholesterol **(Has conjugated double bonds=much less stable) -The ring breaks from UV light which forms previtamin D3 to Vitamin D3 (Cholecalciferol) *This is then picked up by the liver |
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How does Vitamin D3 get picked up by the blood to go to the liver?
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-Chylomicron --> Absorbed in the diet from intestine
-Bound to a protein (VDBP) --> Made from the skin |
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What does the liver do with cholecalciferol?
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-Cholecalfierol (Vit. D3) interacts with 25 hydroxylase (CP450 reaction)
-25 OH D3 leaves the liver and is sent to other tissues but mainly its taken to the kidney |
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Where does CP450 and 25 hydroxylase occur?
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Liver mitochondrial organelles
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What is measured in the blood for vit. D status?
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25 OH Vitamin D3
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What is the most active vitamin D form?
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1,25-OH Vit.D3 (Can either function in the kidney directly or released to other tissues to have an effect peripherally)
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What does the kidney do in Vit. D synthesis?
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-25 OH D3 gets converted to 1,25 OH D3 by the 1 hydroxylase enzyme found in the kindey
-24 hydroxylase can then make either 1) 24,25 OH D3 from 25 OH D3 2) 1,24,25 OH D3 from 1,25 OH D3 |
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What does the parathyroid hormone induce?
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The kindey's production of 1-alpha-hydroxylase
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What are other tissues that have 1-alpha-hydroxylase unrelated to?
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-Calcium metabolism (Not stimulated by the parathyroid hormone)
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What happens when there is a rise in 1,25 OH D3?
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-Reacts with the Vitamin D receptor (non-nuclear) which interacts with genetic material of the cell
-This increases transcription of calbindin (produced on the E.R.) -Calbindin migrates to the villi of the intestine to enhance Ca absorption |
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How can vitamin D act like a hormone?
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-Calcitriol (1,25 OH D3) in the kidney binds to its VDR (a nuclear receptor
-While this is happening, retinoic acid binds to its nuclear receptor to form a heterodiamer -Both bind to the VDRE (vitamin D response element) -The binding creates transcription in a gene of some protein (changes in protein synthesis) |
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What is calbindin?
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-Ca binding protein produced by the parathyroid hormone
-It responds to a drop in blood Ca by causing direct effects on the bone (resorption) or stimulates the kidney to increase 1-alpha-hydroxylase *1.25 OH D3 can increase resorption of Ca from bone and increase the intestinal absorption of Ca in the intestinal tract ***Calcitonin has opposite effects |
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How much vitamin D can be made by direct sunlight on arms and legs for 5 to 10 mins?
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3000 IU
*Fish contain 6000 IU |
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Which ray does not penetrate deep?
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-UVB causes burning not pigment
*Humans need UVB and it is filtered in tanning beds |
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What are non-skeletal diseases that can be helped by the addition of vitamin D?
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-Cancer
-Vascular disease -Infectious disease -Autoimmune disease -Type II diabtetes -Obesity -Cognitive Decline |
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What does the Institute of medicine say should be our daily intake of vitamin D?
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-600 IU for healthy individuals to age 70
-800 IU for individuals age 71 and older ***Evidence is inconsistent, inconclusive, and insufficient to serve as a basis for DRI's |
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What are anti-cancer properties of Vitamin D?
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-Inhibits proliferation
-Enhances differentiation -Enhances apoptosis (unlike necrosis because it doesn't release dangerous compounds to other cells) -Inhibit angiogensis -Enhance "contact inhibition" (Tells cells to stop dividing and prevents pilling of cells) |
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What effect does vitamin D have on cancer?
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-Decreases colorectal cancer (with both an intake and production individually)
-Slightly decreases prostate cancer (only with production) |
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What effect does Ca have on cancer?
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-Decreases the risk of colorectal cancer
-Increases the risk of aggressive prostate cancer |
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What does an increase of Ca cause in the kidney?
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-Decrease in 1,25 OH D3
(The Parathyroid hormone will inhibit 1-alpha-hydroxylase when there is a rise in Ca) *1,25 is only effected in the kidney, other tissue levels of 1,25 will remain normal |
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What in the kidney can act like an endocrine hormone?
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1,25-OH D3
***In other tissues, this only acts locally |
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Why does an increase of Ca cause an increase in prostate cancer?
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-Prostate cancer cells lack 1-alpha-hydroxylase so it relies on the kidney to supply it with 1,25 OH D3
-Because there is a low production of 1,25 in the kidney because of high Ca levels then there is less 1,25 sent to the prostate |
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What are the main mechanisms by which the body tries to increase serum levels of Ca?
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-Increasing bone resorption
-Increasing reabsorption of Ca from the kidney -Increasing absorption of Ca from the GI tract |
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How does 1,25 OH D3 increase intestinal absorption of Ca?
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-By increasing intestinal cell synthesis of Calbindin (transport protein of Ca)
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What does the parathyroid hormone do with relation to Ca?
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-Ca resorption from bone
-Ca reabsorption in the kidney ***response of these increase when Ca levels are low |
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What hormone inhibits bone resorption?
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-Calcitonin--->This helps to keep Ca levels in balance
*In balance with the PTH |
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Where is Trabecular bone found in high levels in the body?
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-Pelvis
-Vertebrae -Ends of long bones |
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What is a DEXA scan?
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-Dual Energy X-ray Absorptiometry
-Can measure soft tissue (muscle and fat) -Can be used on the entire body or just a specific area -Most accurate test of body composition |
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How does a DEXA scan work?
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-Measures in pixels (g/cm2) to obtain a 2-D area
-The pixel is used to determine the weight of Ca below the pixel *Used to make T-values (amount of standard deviations away from the norm) |
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What are the functions of osteoblasts?
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-Bone building cells
-Regulate osteoclasts -Secrete M-CSF and RANK-L -Secrete osteoprotegerin |
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What are the functions of osteoclasts?
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-Stimulate bone resorption
-Secrete acids and enzymes that break down bone in the TB region |
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How are osteoclasts formed?
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-Osteoblasts secrete RANK-L and M-CSF
-RANK-L binds to RANK receptors on the macrophage to form the precursor of an osteoclast -The macrophages are stimulated by this binding of RANK-L and differentiate into mature osteoclasts and proliferate |
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What are resorption pits?
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-Pits formed by osteoclasts where Ca has been dissolved
-They will also be the place where bone will be rebuilt ***Breaking down bone is faster than rebuilding bone |
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What are the functions of OPG?
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-Binds to RANK-L and prevents it from binding to RANK
*Estrogen can also do this -Enhances osteoclast apoptosis |
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How do osteoporosis drugs work?
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-Bisphosphonates that sit in resorption pits for a long time (Ex: Boniva and Fosamax)
-Bind tightly to hydroxy apatite -Promote osteoclast apoptosis (Thought to create calcified regions then can be more prone to break but the risk is a lot less than an osteoporisis break) |
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What is Type 1 diabetes caused by?
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-Inability of the beta cells of the pancreas to produce insulin
***Insulin dependent, autoimmune disease, ketoses prone, juvenile diabetes |
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What are the criteria which would consider someone to have metabolic syndrome?
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-Abdominal obesity (android = type II diabetes) --->Male WC > 40 inches and Women > 35 inches
-Fasting glucose greater than or equal to 110 and lower than 126 mg/dl (impaired fasting glucose) -Blood pressure greater than or equal to 130/80 mm/Hg -TG greater than or equal to 150 mg/dl -HDL ---> less than 40 mg/dl in men and less than 50 mg/dl in women ***3 or more is a predictor of insulin resistance and metabolc syndrome |
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What are factors that can create an insulin resistance?
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-Obesity
-Sedentary lifestyle -Genetics -Aging |
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What can increase as a result of insulin resistance?
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Free fatty acids circulating in the blood that are released from adipose tissue by hormone sensitive (intracellular) lipase
***the lipase enzyme becomes unregulated |
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What is caused by an increase of gluconeogenesis from insulin resistance?
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-Decreased uptake of glucose in the muscle and adipose (decrease in GLUT 4)
-Spike in insulin after meals and glucose remains normal |
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Where is subcutaneous fat not directly sent to?
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The liver
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What happens if there is too much glucose in the blood?
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It can react with amines because it is a reducing sugar which can cause microvascular damage
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What are the metabolic effects of insulin?
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-Increase glycogen synthesis (liver and muscle)
-Increase glucose uptake (muscle and adipose tissue by GLUT 4) -Decreased production of glucose in the liver (decreased glycogenolysis and gluconeogenesis) -Decreases free FA in the blood (inhibits intracellular lipase) -Indirectly increases TG synthesis in adipose (clears TG from the blood by using lipoprotein lipase) -Stimulates uptake of amino acids |
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How does insulin indirectly increase TG synthesis?
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-Insulin induces lipoprotein lipase and provides substrate for TG synthesis
***lipoprotein lipase (found on the extracellular lining of blood vessels of adipose tissue) becomes activated by apoC2 and the chylomicrons and VLDL that came from the liver. The lipase acts on the TG to release it from the VLDL or chylomicron. The lipase is then broken down and recycled. |
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How does a decrease in the uptake of amino acids have an effect during insulin resistance?
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The amino acids are not being taken up by peripheral tissues which means there is more substrate for gluconeogenesis
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What is inflammation?
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A metabolic immune response to injury, illness
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What is omental fat?
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-Intra abdominal fat around the stomach and intestines
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What is mesenteric fat?
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-Intra abdominal fat around the jejunum and illeum of the small intestine
*Change in these adipocytes can have an immediate effect on the liver because they are connected to the portal circulation |
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What is a cytokine?
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A regulatory protein produced (primarily) by cells of the immune response.
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What is an adipokine?
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A regulatory protein produced by adipocytes
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What is obesity?
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A state of chronic low grade inflammation
*inflammatory response, not an accumulation of fat |
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what does a macrophage do with regards to obesity?
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Infiltrates adipose tissue which have produced cytokines and adipokines
*1st indication that obesity is an inflammatory response |
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What is the role of TNF-alpha?
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-Promotes insulin resistance (increased in obesity)
-Can have dramatic effects on metabolism an energy ( increase can stimulate a wasting disease seen in AIDS. colon cancer, and lung cancer) *cachectic factor-->causes wasting -Can be an inflammatory mediator |
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What is the role of IL-6?
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-Promotes insulin resistance (increased in obesity)
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What is leptin's role with regards to adipokines?
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-Suppresses appetite (increased in obesity and leptin resistance may occur from damaged receptors in the hypothalamus)
*Produced by adipocytes when energy stores are full |
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What is the role of adiponectin?
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-Stimulates insulin sensitivity (decreased in obese people)
-Anti-inflammatory -Stimulates FA oxidation |
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What can be used as a marker for inflammation?
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CRP
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How does insulin work?
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-Insulin binds extracellularly to the alpha subunit of the insulin receptor
-This binding causes the beta subunit (which tranverses the membrane) to undergo autophosphorylation -The beta subunit becomes an activated kinase and phosphorylates the cell (particularly the tyrsoine residues) -The phosphorylated residue is now an activated kinase and can phosphorylate insulin receptor substrates in the cell which can then phosphorylate other compounds (such as lipoprotein lipase and GLUT 4) **Insulin receptor substrates that are phosphorylated mediate everything that insulin does |
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How do TNF-alpha and IL-6 induce insulin resistance?
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-They interfere with the ability of the beta-subunit to phosphorylate other substrates in the cell (Ex: The phosphorylation of tyrosine residues)
***They don't effect the binding of insulin to the alpha subunit or the autophosphorylation of the beta subunit |
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What is a possible reason for the inflammatory response to obesity?
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The inflammatory response may be an attempt to protect the body from reaching a point where obesity would impair mobility due to resisting anabolism and favoring catabolism
*Decreases insulin as a defense mechanism to decrease storage |
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What is enzyme induction?
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-An increase in the amount of enzyme (an increase in the protein synthesis of the enzyme)
-An enzyme inducing agent is a substance that increases the synthesis of an enzyme *Happens slowly (Ex: Benzopyrene metabolized in the body (cancer causing form) can be induced by enzymes in cruciferous vegetables to enter Phase II metabolism |
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What is covalent modification?
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-Modification of the structure of an enzyme in order to change the enzyme's activity by either activating it or deactivating it
(Ex:Protein kinase phosphorylation) |
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What is allosteric modification?
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-
-A second messenger is used to bind to an allosteric cite of an enzyme (Ex: Fructose 2,6 bisphosphate is a positive allosteric modulator of PFK-1) ***cAMP = postive allosteric modulator of protein kinase |
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What is enterohepatic circulation and what role does it play in metabolism?
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-The movement of substances from the GI tract, to the liver via the portal vein, and then back into the GI tract via the bile
-This is a major route for “recycling” of bile acids. -Approximately 90% of bile acids are reabsorbed in the ileum, taken back to the liver and then re-used in the bile. |
