Phm142

Colloid containing [cells: erythrocytes, wbc, platelets] [free proteins: albumin, ferritins, clotting enzymes, hormones], and electrolytes

• flexible, biconcave structure
• 95% of cellular protein is HB
• variety of transporters on membrane
• 35-50% hematocrit [ volume of RBC in blood]
• no cell organelles, thus no repair/translation of proteins
• only participates in glycolysis [no oxidative phosphorylation]

Hematocrit stays the same (as volume of RBC should remain the same), but hemoglobin levels should drop (as hemoglobin accumulation phase is rushed)

• Myoglobin+Hemoglobin: both made up of high % of a-helices. 
• Myoglobin: 1 amino acid chain, 1 heme group, hyperbolic saturation curve
• Hemoglobin: 4 a.a. chains, 4 heme groups, sigmoidal saturation curve (thus, co-operativity)

• aka Fe(II)-protoporphyrin IX
• cyclic tetrapyrole (the 4 nitrogens co-ordinating in the plane of heme are from these tetrapyrole groups)
• makes 6 co-ordinating bonds (4 to in plane nitrogens, 1 to HisF8, and 1 to O2)

• Fe-> reused (transferritins)
• Globin-> Broken down and reused by peptidases
• Heme-> Bilirubin

• Lung: 100 torr
• Tissues: 20 torr
• Working Muscle: 5 torr
• p50 Myoglobin: 2.8 torr

Binding of ligand at one site alters binding of ligands at a distal site

• Measure of co-operativity
• y vs. x= log (y/y-1) vs log pO2

• where y= (number of binding sites occupied/ total number of binding sites)
• Slope of 1= no co-operativity
• Slope>1= co-operativity
• 0<Slope<1= negative co-operativity. 
• If the slope= the number of total binding sites, it insinuates instant co-operativity.

• Proposed the T-state(deoxy) and R-state(oxy) nature of hemoglobin.
• Iron binding O2 is pulled into the plane by 0.4 Angstroms, this shift is transmitted to distal co-ordinating bond of HisF8 (which in turn shifts 0.6A), causing a change in formation.
• As a result, HisE7 crowds around O2, stabilizing it
• In t-state, D94(aspartic acid) and H146 are together in space, thus this interaction needs to be overcome for the first O2 to bind (subsequent O2 doesn't need to break this interaction)

• His146 and D94 are together in space in T-state, which creates an interaction; needs to be overcome for O2 to bind
• HisF8 is the distal histidine which shifts 0.6A as a result of Iron being pulled into the plane 0.4 A when O2 binds
• HisE7 stabilizes bound oxygen as a result of the HisF8 conformational change.

• Hemoglobin's oxygen binding affinity is inversely correlated to both Carbon dioxide and acidity (i.e. lower pH= less O2 binding).
• Thus at the same pressure, more oxygen will be released with increasing acidity,or increasing [CO2]

Isohydric transport: CO2 converted to bicarbonate in order to more efficiently expel CO2 [80% of total CO2]

Chloride Shift: bicarbonate ion exchanged with chloride ions to maintain electrical neutrality across RBC membrane.

Venous, due to chloride shift.

• Synthesized as a side rxn of glycolysis
• Decreases O2 affinity by stabilizing T-state(remember that T-state has a larger BPG binding pocket in the middle of Hb) through cross linking of B-chains (salt bridges)
• BPG is the first response to drastic changes in elevation (RBC counts will change over weeks, BPG can be synthesized to a saturation altering level in 2 days)

• Found in lungs and RBCs
• Catalyzes the rxn: 
• H2O + CO2   <->  HCO3- + H+

2,3-BPG is a side reaction from glycolysis.

• BPG is an overall very negative molecule with 5 -ve charges; these charges bind electrostatically to the B-chains (as opposed to the A-chains)in HbA T-state. 
• Electrostatic interactions take place at Lys82, His2, and His143
• One molecule of BPG binds per hemoglobin tetramer. 
• Fetal HbF doesn't bind BPG as well (as it's composed of 2A and 2delta chains)

2 Pyruvate, 2NADH, 2ATP

• 1. Supplies ATP
• -RBC have 30-40 mins of energy reserve of ATP; majority used for Na/K transport, and Ca/ATPase, and some used to maintain glycolysis
• 2. Supplies NADH for methemoglobin reductase (converts Hb3+ -> Hb2+)

• Pumps sodium out of cell, pumps potassium in to cell
• Can be inhibited by digitalis and ouabain

• Constantly uses energy to pump Calcium out of cell
• Increased intracellular calcium is indicative of cell membrane damage and aging of the cell (this aged cell is called an echinocyte)

• Aged RBC (loss of cell membrane integrity=increased intracellular calcium levels)
• Described as crenated, dehydrated cell which are no longer biconcave
• They are removed by the spleen (by the reticulo-endothelial cells/macrophages)

• Glutathione
• GSH reductase
• GSH peroxidase
• Catalase (requiers 4 bound NADPHs to be active)

Arsenate Inhibits net gain of ATP in glycolysis. (fluoride just inhibits glycolysis, not sure how)

6-phosphogluconate->ribulose-5-phosphate (produces a NADPH, and catalyzed by 6phosphogluconate dehydrogenase).

Can isomerize into xylulose-5-phosphate (ribulose 5 phosphate epimerase) and ribose-5-phosphate (ribose-5-phosphate isomerase); both of these products are precursors to fructose-6-phosphate and G3P

3 R-5-P make 2-F-6-P and 1 G3P

Lecture 1 slide 6

Lecture 1, slide 22

Lecture 1, Slide 11

Lecture 1, slide 21

Lecture 1, slide 13

Lecture 1, slide 23

Lecture 1, slide 26

Lecture 1, slide 31

Lecture 1, slide 39

Slide 39

Lecture 1, Slide 40

• Aspirin (not sure how)
• Dapsone (prototypical MetHb inducing drug)
• Methylene Blue (not sure how, but NADPH required to convert to leucomethylene blue)
• Primaquine (anti-malarial)
• Salicylates (not sure how)

• Outcompetes O2 for heme,
• victims turn bright red
• 25000X affinity for heme, 200X greater affinity for Hb (distal histidine HisE7 makes it harder for monoxide to bind)

• deoxy HB2+ : purple
• oxy HB2+: red
• metHB: brown(rusting)

Oxygen doesn't bind to Fe3+, but causes a conformational change that binds the other 3 oxygens (to the remaining three Fe2+) in a irreversible fashion. Causes a leftward shift of the hemoglobin saturation curve.

• Oxidation of Fe2+ to Fe3+ in hemoglobin (usually by Amyl+ Sodium nitrite). 
• This causes cyanide to bind to the Fe3+ reversibly; as a result, cytochrome C in mitochondria are saved. Really a cost-benefit approach to therapy.

Produced by oxidation of Oxyhemoglobin to Methemoglobin

• Catalase (H2O2-> O2 + 2H2O)
• GSH Peroxidase (H2O2-> H20 by GSH-> GSSG)
• both of these rely on sufficient amounts of NADPH being available. If not hemolysis will occur.

Unit 2, slide 4

Lecture 2, Slide 4

• Destruction of RBCs or their progenitors. 
• Presents as black urine (due to hemolysis) and/or hypoxia (due to large numbers of methemoglobins)
• Frequently seen in G6PD defeciency. 

• Basically any drugs that would create large amounts of ROS ex:
• aromatic amines, nitro compounds, hydrazines, antimalarial drugs, FAVA beans.

Fast: rapid contraction for short duration; primarily anaerobic glycolysis, large glycogen content, small mitochondrial content, little myoglobin

Slow: slow contraction for long duration, primarily oxidative respiration, large mitochondrial content+ blood supply, large number of myoglobin (red meat)

• pretty rare (1/12000 children, 1/45000 adults)
• chromosome 19, ryanodine receptor
• anesthetic produces excessive Ca2+ release causing excessive heat+lactic acid leading to death by acidosis.
• Reversible if caught in the first couple minutes, administer dantrolene.

Lecture 2 Slide 9

Hypochlorous acid is found in WBC to create hydroxyl radicals to destroy pathogens in a generic way

Peroxynitrate has been implicated in inflammaation as well as atherosclerosis.

Lecture 2, Slide 10

• Principal RBC anti-oxidant (concentrations in the millimolar)
• tripeptide of glutamate, cysteine, glycine (cysteine disulfide is the driving force)
• co-factor for many cellular enzymes
• most located in cytosol, some in the mitochondria (obviously not the case in RBCs)
• Detoxifies reactive drug metabolites
• Scavenges free radicals
• maintains cysteine in reduced form(thus allowing for a reservoir of free cysteines)

Specifically cleaves G-glutamyl linkages, for example glutathione (G-glutamyl-cysteine-glycine)

links glutamate with cysteine via a g-glutamyl linkage, using ATP

buthionine sulfoxamine (used in chemotherapy)

It serves to make the final product more water soluble.

Lecture 2, slide 16

• Lecture 2, slide 17
• N-acetyl-cysteine

• x-linked (females=heterozygotes[wild type+affected rbcs], males=affected)
• very common (~400 milli world wide)
• Type 1: <2% enzyme count
• Type 2: <10% enzyme count
• Type 3: 10-50% enzyme count
• Type 4: normal enzyme count 
• 20% is the cutoff for symptoms (thus some type 3 won't exhibit symptoms)

Glucose-6-phosphate -> 6-phosphogluconate

• a) N126D (asparagine to aspartate)
• b) V68M (valine to methionine)
• these mutations occur 8Angstroms apart. 
• If you just have a), you will get a reduction in the G6PDa to 85% [not clinically significant], if you have a) and b) then you 12% G6PD activity. 

b) mutation increases protein rigidity, and affects Lys205, which is the active site of G-6-P binding.

• Plasmodium Falciparum
• attacks RBC by using specialized food vacuole
• can consume 60-80% of Hb (using its own proteases) in RBC for its own protein synthesis(which will be seen as aggregates called Hemazoin)
• Normal RBC have low glucose utilization, and low lactate formation, but malaria parasite will instill its own hexokinase, and make large amounts of atp + lactate(30X more glycolysis than average RBC) (using up glucose) to create its own RNA/DNA/Protein

G6PD protects against oxidative stress by creating NADPH. In deficiency, increased oxidative stress due to large amounts of free iron & lack of reduced GSH will lead to hydroxyl radicals that will attack the malarial infection.

Lecture 2, slide 27.

Lecture 2, slide 29.

Lecture 3, slide 1

• divicine
• redox
• gsh
• NADPH

• Found mostly in blacks (10-25%), and some brown people (1%)
• Glutamate to valine substitution at position 6 of B-chain of Hb.

The valine substitution wants to avoid water, attracts other Hb molecules. These stacks keep growing until they hit the wall of the RBC, creating a sickled look. 

Sickling is not apparant until times of oxygen debt (T-state)

14 stranded braid stabilized by multiple interactions

• Aggregation of the hemoglobin causes sickling. When passing through capillaries, sickled cells will lose K+.
• These sickled cells are removed from circulation more rapidly by the spleen.

Heterozygotes for sickle-cell disease have altered potassium content in their RBC

When RBCs pass through capillaries, they sickle and lose potassium, however malaria needs high potassium conditions to survive.

Sickling is triggered by conditions that prolong capillary transit (i.e. abnormal adherence to endothelium).

This implies that if capillary transit time, when HbS is in deoxygenated state, is less than fibril formation lag time, then sickling will not occur. 

• No adequate treatment for primary disease.
• Can administer hydroxyurea, which promotes the production of HbF (promotes Gammaglobin synthesis), which doesnt stack as readily as HbA
• However secondary diseases can be prevented
• -vaso-occulusive crises/stroke-shown as cloudyness or decreased vascularity in the white of the eye
• -manage chronic pain symptoms
• -manage chronic anemia
• -prevention and treatment of primary infections [say diabetes+sickle will need more aggressive treatment]

• Group of diseases resulting from genetic defects in synthesizing one type of Hb chain (either A or B)
• -can form A4 tetramers and B4 tetramers which have weird dissociation curves
• Can lead to ineffective erythropoiesis, hemolysis, and possibly anemia

• Alpha thallasemia- can't produce A-chains, thus excessive B and Gamma chains seen, causing a variety of abnormal HB (very similar to hydroxyurea + sickle cell Hb)
• Beta thallasemia- Can't produce B-chains, excessive formation of A4 tetramers, and HbF

Can use splenectomy (reduces the number of RBC that will be destroyed) or allogeneic hematopoietic stem cell transplantation 

Do not use transfusion therapy, as these rbc will eventually die too, leading to even more iron and free radical production (if it has been done, use chelation therapy to reduce the damage)

• Blood (32 ug), Liver (13 ug), Bone marrow (4 ug)
• Note how approximately 60% of body iron is bound to heme.

Inclusions within RBCs composed of denatured Hb. Can be seen in hemolytic anemia, or in RBCs subject to large amounts of oxidative stress

Allows iron to be brought in past the brush border in Fe2+ state (without being oxidized/turned into something else). This reaction requires vitamin C. thus the role of vitamin C in facilitating Fe absorption.

Breaks down Heme. Found in proximal duodenum cells. 

Heme -> Carbon + billiverdin + free iron

Catalyzez the conversion of Fe3+ -> Fe2+ in proximal duodenum cells.

Hephaestin does the reverse, i.e. Fe2+ -> Fe3+

• Lecture 3, slide 13
• 1. Iron/heme released from food, chelated by compounds that keep them soluble (Fe2+ state by ferroreductase)
• 2. Uptake occurs in proximal duodenum (but only about 10% of dietary Fe is absorbed)
• 3. Iron enters as either inorganic ion (Fe2+) or heme (which is broken down by heme oxygenase)
• 4. Iron either stored in ferritin (hephaestin converts to Fe3+) or exits cell via ferroportin transporter (after conversion by Hephaestin) and gets picked up by transferrin to distribute to tissues.

25 a.a. peptide hormone produced in liver that inhibits ferroportin transporter.

• Responds to acute phase infections. 
• Trapped iron inside cells is liberated when cells are sloughed (remember that intestinal cells have a quick turnover rate)

Low dietary iron (this is the only one that will not decrease hepcidin levels)

• Low body iron
• increased RBC production (anemia)
• low hemoglobin
• low blood oxygen content.

Systemic inflammation(infection)-> increased hepcidin

• Very large protein (450,000MW; 24X175 a.a. chains)
• Holds 4500 irons/protein (FeOH3- note how the iron is in Fe3+ form)
• synthesized and secreted by the liver
• protects body from free iron toxicity
• 60% glycosylated(helps to maintain host-protein status and provides stability)
• Normal saturation is about 20%, iron overload~35%
• Iron is released by reduction, and chelation, and taken into cell by endocytosis

• alcoholism causes decreased transferrin-bound iron uptake.
• as a result, get an increase in ferritin receptors, and increased hepatocyte iron overload.

• MW 76000 (still big, but not as big as ferritin)
• 679 a.a. (2 mols Fe3+/mol Tf)
• 6% carbohydrate sugars decorate surface to increase longevity/decrease immunity (much like ferritin)
• Transports ~25mg/day (95% of blood plasma iron from catabolized RBCs)
• Transfer ~22mg/day to Hb
• Typical saturation is 20-25% (overload is ~33%)
• Taken up by hepatocytes, bone marrow, placenta via transferrin receptor.

• 1) Iron loaded transferrin binds to transferrin receptor (the carboxy side with carbohydrate moieties) causing conformational change due to energy of binding
• 2) Conformational change causes internal proteins(clathrin) (at amino-terminus ends) to coat inside of cell surface
• 3) Endocytosis occurs via invagination and a vesicle coated with clathrin is created
• 4) Coated vesicle proteins disassemble, creating endosome
• 5) Endosome pumps in protons(using ATP), which changes the nature of electrostatic interactions between transferrin and Iron, which releases the iron. 
• 6) Free iron either gets picked up by proteins (ex. ferritin) and the receptors concentrate in an arm-like extension of the endosome and are returned to the cell surface.

• mRNA.
• Low cellular Fe: TfR mrna increases stability which leads to increase receptor proteins.

• Stem-loop structure in non-coding region of mRNA
• Unpaired C(in the stem) and C-A-G-U-G-C (is the entirety of the loop) sections are conserved. 

Binding of these elements will alter translational efficiency (of ferritin and transferrin receptor-> controls level of iron stores and iron transporters)

Low cellular iron causes IRP(rotein) to bind ferritin mRNA at the 5' end at the site of the IRE, preventing translation

High cellular iron causes release of IRP from stem-loop IRE because iron will bind the IRP instead (thus iron is directly involved in controlling its own levels)-> as a result, translation can proceed .

Important to note that transcription of genes is still the same, but only the translation of RNA is affected. Thus translational efficiency is affected.

For TfR mRNA, IRE is located on 3' end. 

Increased free iron causes iron to bind IRP, exposing IRE+poly-a-tail to degradation, thereby decreasing translational efficiency

Decreased free iron causes IRP to bind the IRE at the 3' end, protecting the poly-a-tail from degradation, increasing mRNA half-life, thus increasing translational efficiency.

• Direct blood loss (chronic/acute)
• RBC destruction
• -extrinsic: dietary/environmental/drug induced
• -intrinsic: genetic, HbS, thallasemia

Bone marrow abnormalities (hypochromic/mycrocytic anemia)

Eating phytates (cereals, nuts, legumes, soybeans), polyphenols (tea, vegetables), Tannates (tea, coffee, veg)

Low meat intake

Lack of vitamin C

(Best way) If you find a low serum ferritin count (which is usually seen in acute/chronic inflammation), and high amounts of transferrin+transferrin receptor.

• (Additionally) Hb will be low, and there will be an increase in protoporphyrin levels in RBC (due to not finishing Hb molecules in  the protein accumulation phase)
• There will also be decreased serum iron (but this is the least indicative of everything, as this can be low for a variety of reasons)

Ferritin levels increase (to lock up available iron), and transferrin levels decrease (to not allow iron into cells)

Ferritin levels are low (just not enough iron), and transferrin levels are high (trying to mobilize available iron)

Vitamin c(increase absorption of non-heme iron), Lactoferrin (whey proteins in milk/cheese, complex to non-heme Fe)

Basically if you want to avoid the mucosal block of the gut. (IBD, ulcers, etc. )

May lead to iron overload, may cause allergic reaction

• tetracycline, penicillamine, levodopa, quinoline
• (pretty sure this would happen in the gut, thereby decreasing absorption)

• Heriditary hemochromatosis (Recognizable as a bronz-y tan, along with a bronze glow in the eye)
• Induced hemochromatosis (giving transfusions when you see decreased RBCs, but they may have thallasemia or HbS so more RBC get destroyed, releasing free iron)
• Alcoholic cirrhosis, oral iron therapy,

Do not have sufficiently developed mucosal lining, thus cannot limit free iron absorption. 

Victims will exhibit black stools, acidosis, convulsions, comas, and renal failure

Treated with chelation therapy (desferoxamine)

• Occurs due to saturation of transferrin stores
• Free serum iron will accumulate in liver Kupffer cells, bone marrow, myocardium, pancreas (due to high levels of transferrin receptors) (this is why a lot of haemachromatosis patients will have diabetes/ liver cirrhosis/cardiac dysfunction)

• Phlebotomy
• Desferoxamine (chelating agent) + ascorbic acid (vitamin c)

genetic disorder (Mutation in HFE gene, which codes for transferritin receptor -> increases absorption of iron)

More than 95% of genetically caused iron overloads are caused by this

There are also others which affect hepcidin, transferrin receptor, ferroportin (but again, the main cause will probably HFE gene-> transferrin receptor)

Lecture 3, page 39

Lecture 3, slide 40

• Neural tube defects
• Premature atherosclerosis/inflammation
• Anemia, weight loss, weakness (in elderly)
• G.I., mucosa, and bone marrow complications

• Oral contraceptives
• NSAIDs
• Smoking
• Alcohol (inhibits methionine adenosyl transferase)
• Methotrexate (inhibits dihydrofolate reductase)
• Nitrous oxide (inhibits methionine synthase)

• Hyperhomocysteinemia patients
• Ulcerative cholitis (Increased colon cancer)

Pteridine (5N) moiety, PABA (10N), L-glutamic acid, Poly-glutamate side chain

The folyl/pterolyl moiety is the workhorse of the molecule (Pteridine+PABA)

Pteridine, PABA, gamma-glutamyl linkage between PABA and L-glutamate

Lecture 4, page 7

Methanol is metabolized to either formalin (causes blindness) or formate (can be fed into THF derivative synthesis to create 10N-formyl-THF)

Lecture 4, slide 29

It can recreate folic acid precursors without the need for dihydrofolate reductase.

Alcoholism inhibits methionine adenosyl transferase, causing those downstream effects via remethylation cycle and homocysteine deficiency.

Also, some oxygen radicals can inhibit methionine adenosyl transferase as well (hypoxia, liver cirrhosis, septic shock)

lecture 4, page 16

vitamin b12 deficiency, not allowing methionine synthase to convert homocysteine-> methionine.

Hyperhomocysteinemia

Increasing DNA synthesis requires an increase in Guanine and Adenosine. These are created when 5/10 formyl THF and 5,10-methenyl THF donate their 1 carbon groups. Since formyl THF requires formate for its creation, the equilibrium for methanol metabolism will favour its production (as opposed to toxic formalin).

aminopterin/Methotrexate is a competitive inhibitor for DHFR.

fluorouracil is a suicide inhibitor for thymidylate synthase due to its electron withdrawing effects (fluorine)

Myelosuppression (decreased marrow activity) and mucositis (inflammation of digestive tract)

Folinic acid/leuocovorin

• Lack of folate
• Lack of homocysteine
• Lack of B12
• Nitrous oxide anesthetic

• Can be due to deficiency in B6, B12, B9
• Genetic deficiency (MTHFR,methionine synthase, cystathione b-synthase[autosomally recessive disorder with the hallmark of lens dislocation, cns and skeletal dysfunction])

CBS is located on chromosome 21, trisomied in Down's syndrome-> thus overexpression.

Increased levels of homocysteine, elevated cystathione and hypermethylation

Cobalt-containing compounds possessing a corrin ring (4 co-ordinating bonds- 4 to ring nitrogens, 1 to a non-ring nitrogen, and 1 to a variable group [-OH, -CN, -CH3, adenosine])

Required for 3 enzymatic reactions: methinone synthase, methylmalonyl CoA mutase, leucine aminomutase

• Cyanocobalamin (B12 supplement)
• Hydroxocobalamin (cyanide+sulfide poisoning)
• Deoxyadenosylcobalamin (amino acid metabolism)
• methylcobalamin (for methylation [homocysteine-> methionine] )

Cobalophillin (secreted from salivary glands) binds available B12 in saliva, protects from stomach acid hydrolysis

This complex gets hydrolyzed in duodenum, and binds to intrinsic factor (a glycoprotein)

Only IF/B12 complex can be absorbed (neither can be absorbed individually) in distal third of ileum

Cause for deficiency is usually impaired complexing of B12/IF (either autoimmune or genetic-> both due to duodenal damage)

• Transporter by transcobalamin 2 in blood
• Stored bound to transcobalamin 1 and 3

• Decreased carboxylate carrying capacity of mitochondria-> severe growth retardation
• Decreases THF levels -> decreased DNA synthesis-> pernicious anemia (pale look)

Pale, shiny tongue (lack of DNA synthesis effecting g.i. tract [glositis] )

this deficiency common in gastectomy patients (removal of duodenum/ileum)

Nitrous oxide (N2O) causes oxidation of cobalt(I) to cobalt (II) which will inhibit this enzyme.

Arises under conditions of B12 or IF defeciency.

Decreased B12 causes decreases folic acid (secondary effect), leading to impaired erythropoiesis, leading to premature release of erythrocytes (megaloblastic anemia-> can see nuclear material in RBCs)

Can be treated readily (within 72 hours) with B12 supplementation.

Lecture 4, slide 25.

Lecture 4, slide 18

Lecture 4, slide 24

Lecture 4, slide 16.

Polysaccharide cell surface makers on RBCs

everyone has antigen H, modification to it will be A or B, unmodified results in O.

O=universal donor, can't except unless from O

Ex. Bloodtype A has antibodies to B; bloodtype O has antibodies to both A and B; bloodtype A/B doesnt have antibodies to A or B

• lack/lowering of granulocytes (especially neutrophils, and also eosinophils and basophils) in blood. 
• 75% of cases are drug induced. 
• ex. of drugs: Anti-inflammatory, Anti-thyroid/Thionamides, Cardiovascular drugs, Psychotropic drugs (TCA), Antibiotics, Dermatologic drugs (dapsone)

Signs and symptoms: often asymptomatic, may present with sudden fever, sore throat, septic shock. Higher chances of infection

• Pathogenesis:
• Direct toxicity: drug's reactive metabolite directly binds to neutrophils/their reserves in bone marrow
• Immune mediated: 4 different mechanisms

Treatment: Neutrophil recovery, like hematopoietic growth factors like G-CSF (granulocyte colony stimlating factor) and GMCSF (granulocyte macrophage colony stimulating factor)

• symptoms: headache, drowsiness, vomiting, bloody urine, changes in fingernail pigmentation
• can be inhaled/ingested and mainly distributes to the liver
• carcinogenic due to oxidative stress (inhibition of glutathione), inhibition of p53, genotoxicity, altered DNA repair and tumour promotion

arsenite, trivalent (As3+) reacts with thiols, and blocks GSH reductase-> increased free radicals; Inhibits pyruvate deoxygenase (decreased citric acid cycle activity)-> Decreased ATP and gluconeogenesis

Arsenate (pentavalent As5+): replaces phosphate groups (thus ADP-arsenate, rather than ATP; glucose-6-arsenate rather than G6P; g3-arsenate rather than G3P)

Can be treated with DMSA

Coagulation is the process of blood clot formation (aka thrombogenesis)

Warfarin: vitamin K antagonist; interferes with hepatic synthesis of coagulation factors

Heparin: indirect thrombin inhibitor; increases endogenous antithrombin activity

• Apixaban: direct factor Xa inhibitor
• Dabigatran: direct thrombin inhibitor

Glycogen synthase extends glycogen chains (forms α -1,4 glycosidic bonds) (glycogenesis); glycogen phosphorylase breaks those bonds(glycogenolysis).

• type 0: deficiency in glycogen synthase in muscle/liver
• Type 1 (most common): glucose-6-phosphate or g-6-p transporter deficiency. 
• Type 2: deficiency of the enzyme alpha-1,4-glucosidase in lysosomes
• type 3: inherited: buildup of abnormal glycogen due to deficiency in debranching enzyme
• Type4:  inherited: buildup of abnormal glycogen due to deficiency in branching enzyme
• Type 5: inherited: inability to break down glycogen in muscle cells (deficiency in myophosphorylase enzyme)
• Type 6: deficiency in liver glycogen phosphorylase, causes liver enlargement due to buildup of glycogen
• Type 7: deficiency in phosphofructokinase specific to muscles.

• Basophils = granulocytes that release chemicals to promote inflammation
• Eosinophils = granulocytes, cytotoxic killers that primarily target parasites
• Neutrophils = phagocytic granulocytes that ingest and kill bacteria
• Monocytes/macrophages = phagocytic antigen-presenting cells that ingest pathogens and activate helper T cells
• B-lymphocytes = antigen specific cells that have NOT come in contact with their antigen
• Plasma cells = activated B lymphocytes that have been in contact with their antigen and produces specific antibodies
• Memory B cells = inactive B lymphocytes that have been in contact with their antigen and remains in body in the event of secondary exposure to same antigen
• Helper T cells = lymphocytes that release cytokines to help activate B lymphocytes
• Cytotoxic T cells = lymphocytes that kill self cells carrying foreign antigens by inducing apoptosis and secreting digestive enzymes and perforin
• Natural killer cells = lymphocytes that target abnormal self cells and induces apoptosis

• -helps to reduce kidney rejection
• -Sirolimus acts on T and B cells of the immune system; Sirolimus binds with FKBP (FK506 binding protein) to form an immunosuppressive complex that inhibits the activity of the protein, mTOR (mammalian target of rapamycin)

By inhibiting mTOR, Sirolimus prevents protein synthesis, synthesis of cell cycle proteins, and translation of mRNAs required for cell growth and proliferation

Warburg effect describes the preferred metabolic pathway exhibited by cancerous cells
oxidative glycolysis

Cells generate ATP through amplified rates of glycolysis and do not go through oxidative phosphorylation as primary pathway of generating ATP, leading to high lactate levels

Lecture 2 slide 15