4. Thesis > Defence Study Sheet > Flashcards

Defence Study Sheet Flashcards

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1
Q

Pharmacodynamics

A

(D=drug)
Branch of pharmacology concerned with the effects of drugs and their mechanism of action/biochemical and physiologic effects
i.e. what the drug does to body at molecular/cellular level

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2
Q

Pharmacokinetics

A

(KIN=body)
Definition: branch of pharmacology regarding movement of drugs in body/how the body affects a specific substance after administration
i.e. what body does to the drug

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3
Q

Metabolism

A

Process of body chemically altering drugs to turn into metabolites that can be eliminated – often involves enzymes

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4
Q

p38 MAPK

A

(Inflammatory signaling protein kinase)
Responsive to stress/immune stimulation; proliferates microglia
Family of signalling proteins found in cytoplasm and nucleus of most eukaryotic cells, acting as a key stress-activated sensor.
pathway is activated by a three-tier cascade—MAP3K →p38 MAPK—driven by environmental stress, inflammatory cytokine, sometimes growth factors
Consequence: p38 activates transcription factors thus promoting gene expression for inflammatory responses, apoptosis (cell death), or cell differentiation

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5
Q

Matrix metalloproteinase (MMPs)

A

Enzymes capable of degrading extracellular matrix proteins, releasing cytokines and apoptotic ligands
Inhibition weakens BBB integrity

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6
Q

Reactive oxygen species (ROS)

A

Byproduct of normal oxygen metabolism, important role in cell signalling; associated with cell damage in excess due to reactivity
Antioxidant systems prevent ROS being formed or remove them
reactive oxygen species can be beneficial, as they are used by the immune system as a way to attack and kill pathogens

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7
Q

Antioxidant

A

Inhibit oxidation, the chemical reaction that produces free radicals

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8
Q

IL: interleukins

A

Type of cytokine. Proteins produced by blood and endothelial cells

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9
Q

Cytokines

A

Small soluble signalling proteins; secreted by immune cells and non-immune cells like endothelium.
Maintain innate and acquired defence and regulate homeostasis via pro/anti inflammatory effects
Function as messengers between cells during immune response; not just markers but active in disease mechanisms
Recruit more macrophages/immune cells to site to perpetuate response

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10
Q

Chemokine

A

Cytokine subset that regulates movement of immune cells (chemoattractants) to guide immune cells
Both homeostatic (CCL-14 up) and inflammatory (IL-8, CCL-2 etc.)

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11
Q

Oxidative stress

A

imbalance between production and accumulation of oxygen reactive species (ROS) in cells and tissues and the ability of a biological system to detoxify these reactive products
Markers: glutathione, Nitric oxide metabolites (NOx)

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12
Q

S100B

A

Calcium binding protein; expressed by astrocytes; marker of glial activation and BBB permeability

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13
Q

Enzyme linked immunoabsorbant assay (ELISA)

A

Works by detecting and measuring specific substances (e.g. proteins, antibodies) in a sample via colour chart concentrations
1) Plate coated with a capture antibody with specificity for target substance
2) Sample added, if target present binds to capture antibody.
3) Unbound materials washed away
4) Detection antibody linked to an enzyme is added; binds to the target
5) Substrate added and reacts with enzyme; causes visible color change or fluorescence
6) Intensity of signal indicates amount of target in the sample; compared to a standard curve to quantify concentration

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14
Q

Plasma

A

Liquid left after centrifuging blood with anticoagulant; separates from cells blood cells are absent, but contains proteins and other constituents

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15
Q

Serum

A

Clear, yellowish, fluid that remains from blood plasma after blood cells and clotting factors/coagulants removed (e.g. fibrogen)
Used in antibody research
Distinct from plasma because does not contain clotting factors

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16
Q

ELISA alternatives

A

High performance liquid chromatography (HPLC)
Multiplex LUMINEX - 5x more expensive but cost effective if many markers
Multiplexed bead-based flow cytometry, e.g., cytometric bead array, can simultaneously evaluate different soluble cytokines on a robust platform.

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17
Q

Why plasma samples

A

Allows temporal tracking of signalling molecules (i.e. what is the inflammatory signal at that time)
More accurate in vivo measurement than serum because avoids confounding from coagulation/clotting-related release of platelet-derived cytokines (e.g. CXCL4)

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18
Q

EDTA plasma

A

Centrifuged blood collected in lavender top EDTA tubes
Prevents clotting by chelating calcium
Chelator anticoagulants like EDTA and citrate salts work by binding calcium

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19
Q

Why EDTA plasma for cytokine assessment

A

Gold standard for accuracy, reducing variability
Higher sensitivity for low-abundance cytokines

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20
Q

Buffy coat

A

Thin layer of leukocytes and platelets that forms between RBCs and plasma when anticoagulant-treated blood is centrifuged
Pink/red because rarely 100% pure, almost always contaminated with residual RBCs

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21
Q

Why Buffy Coat sample

A

For Immune cell analysis (I.e. what are the immune cells doing at that time)
Contains 10–20 times more WBCs than whole blood; highly concentrated source of lymphocytes, monocytes, and granulocytes

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22
Q

FDA biomarker categories (BEST)

A

Diagnostic
Prognostic
Predictive
Pharmacodynamic/response
Safety
Monitoring
Risk/susceptibiity

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23
Q

Primary anti-inflammatory cytokines

A

IL-4, IL-10, IL-13, TGF-beta

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24
Q

Primary pro-inflammatory cytokines

A

CCL-2/MCP-1, IL-1-beta, IL-6, IL-8/CXCL8, IL-12, IL-1, IL-23
IFN-gamma, TNF-alpha

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25
Minocycline pharmacodynamics
-Suppresses microglial activation: by interfering with P38 MAPK signaling pathway and NF-kB translocation -thus: reduced microglial secretion of TNFa, IL-1b, IL-6 -Inhibits neutrophil migration, degranulation, oxygen-radical formation -Glutamate-antagonistic (NMDA and AMPA receptors) -thus: inhibits of p38 phosphorylation and IL-1 release -Anti-apoptotic: inhibits caspase enzyme activity, triggers neuronal cell death -restores BBB integrity: inhibits MMPs which weaken BBB integrity -thus: reduced infiltration peripheral immune cells -Antioxidant: inhibits glutamate release from microglia by downregulating NMDA receptors, downregulates Nitric oxide enzyme - Inhibits NO release -thus: prevents glutamate excitotoxicity and oxidative stress, reduces neurotoxic reactive nitrogen species -Neuroprotection: inhibits inflammatory signaling kinases such as p38 -Stabilizes KYN pathway: inhibits IDO expression by reducing cytokines - thus: restores serotonin synthesis by preventing tryptophan being diverted kyneurine/metabolites, reduced neurotoxic metabolites like QA and KYNA
26
Minocycline pharmacokinetics
-Bioavailability 90-100%: means Quickly and nearly completely absorbed, plasma concentration peaks 1-4hr -thus: quick onset action -Only 5-10% excreted unchanged via urine (i.e. used all of it?) -thus: immediate action, no titration needed, ok for long-term use -Extensive tissue distribution: penetrates/ accumulates most tissues, -thus: addresses intracellular signaling involved in inflammation -Long half-life:11-26 hours - thus: maintains steady therapeutic levels, reduced need for frequent dosing, good for chronic neuroinflammation -Lipid solubility - thus: efficient BBB penetration, acts on microglia / neurotransmission, achieves therapeutic concentrations in CNS
27
Minocycline metabolism
-Metabolized in the liver – excreted unchanged in urine; Drug clearance and efficacy could be impacted if liver dysfunction - Thus: Suggests pharmacological activity largely dependent on parent compound acting directly in the brain after crossing BBB -Does not undergo extensive biotransformation -thus: remains largely intact by time reaches bloodstream and brain -Long elimination half-life (16-22hrs) -thus: maintains consistent drug levels in the body; Steady state concentrations may contribute to efficacy as longer duration of action may provide continuous anti-inflammatory and neuroprotective effects I.e. Limited metabolism means = substantial amount of unchanged drug retained in circulation = prolonged therapeutic effects = well-suited to conditions where neurobiological impact is desired
28
Define cytokine inhibitors
-Less diverse actions, more specialized -thus: not useful alone if exact mechansims involved unclear -Risks: immune suppression, infection susceptibility, autoimmune reactions
29
Issues with NSAIDs/COX inhibitors
Long term side effects: ulcers, cardio, kidney
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Primary minocycline side effects
-Reduced efficacy birth control pills -Bone/tooth development in fetus -Yellowing/greying eyes and teeth -Reduced iron/calcium/mag absorption -Severe skin rash/reaction (photosensistivity) Need to time around CA/NA/MG for absoprtion
31
Minocycline antibiotic actions
-Stops bacterial growth by decreasing ability to make protein By binding to 30S ribosomal subunit of bacteria -thus: only effective against multiplying micro-organisms -Broad-spectrum: affects both gram pos and neg I.e. not a bacterial killer
32
CCL
C-C motif chemokine ligands (chemokine) key pro-inflammatory cytokine that attracts monocytes, T cells, and dendritic cells to sites of injury or infection Acts as a primary chemoattractant for macrophages and monocytes, crucial for immune defense and wound healing Expressed by cells (endo, fibro, tumour) response to inflammatory stimuli like IL-1, IL-6, and TNFa essential for initiating the inflammatory response but can cause hyper-inflammation if overproduced
33
VEGF
vascular endothelial growth factor
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CXC
chemotaxic cytokines (chemokine)
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IFN
Interferon
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NAC
n-aceytlcysteine, antioxidant
37
CRP source
Liver via IL-6, IL-1b, TNF-a
38
CRP role
Part of acute response Facilitates phagocytosis Activates classical complement pathway Non-specific marker of systemic inflammation and tissue damage
39
IFN-gamma source
Th1 and NK cells
40
IFN-gamma role
Activates macrophages Enhances antigen presentation
41
TNF-alpha role
Primary mediator of acute response Activates endothelium increasing permeability Promotes inflammatory cytokines Mobilizes neutrophils Involved in apoptosis
42
TNF alpha source
Macrophages, T-cells
43
CCL-2 (chemokine C-C ligand 2) / MCP-1 source
Macrophages, endothelial, epithelial cells
44
CCL-2 role
Chemotaxis: attracts monocytes, dendritic, memory T cells to site Key in neuro-inflammation; expressed by microglia, neurons, astrocytes
45
IL-1-beta role
Part of acute response Recruits leukocytes, activates endothelium Stimulates cytokines like IL-6 Increases NF-kB signaling Stress related
46
CCL-2 role
Chemotaxis: attracts monocytes, dendritic, memory T cells to site Key in neuro-inflammation; expressed by microglia, neurons, astrocytes
47
IL-1B source
Macrophage, monocyte cells
48
IL-6 role
Part of acute response Stimulates acute phase proteins in liver, neutrophils in bone marrow Differentiates B cells via NF-kB activation
49
IL-6 source
Macrophages, endothelial, T-cells
50
IL-8:CXCL8 role
Key to acute response Chemotaxis: neutrophils, granulocytes Increased by oxidative stress, promotes oxidative burst Induced/reduced by other cytokines
51
IL-8/CXCL8 source
Macrophages, endothelial, epithelial cells
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IL-12 role
Differentiates Th1 and activates NK cells Stimulates IFN-gamma and TNF-a production by NK/T-cells
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IL-12 source
Macrophages, B-cells
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IL-17 source
Th17
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IL-17 role
Recruits neutrophils Promotes tissue inflammation Implicated in neuroinflammation and plasticity
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IL-23 role
Part of IL-12 family Promotes Th17 cells which increases IL-17, 22, 23 Promotes adaptive response
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IL-23 source
Macrophage, dendritic cells
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IL-4 role
*Anti inflammatory Related to adaptive immunity Differentiates Th2 which produce IL-4 in positive feedback Decreases Th1, IFN-g, macrophage, IL-12
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IL-4 source
Th2, mast cells
60
IL-10 role
*anti inflammatory AKA: CSIF (cytokine synthesis inhibitory factor) Downregulates Th1 in favour of Th2 Inhibits IFN-g, IL-2/3, TNF-a Can block NF-kB significant role in suppressing immune responses and reducing inflammation by inhibiting the production of pro-inflammatory cytokines such as IL-6 and TNF-α
61
IL-10 source
Monocytes, Treg, mast cells
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IL-13 role
*can be anti inflammatory Related to IL-4 Promotes M2 polarization, suppresses macrophage cytokine release Inhibits Th1 – reduces IL-12, IFN-gamma With IL-4 promotes Th2
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IL-13 source
Th2 cells
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TGF-B role
*anti inflammatory Suppresses immune response
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TGF-B source
T-reg cells
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Cytokines increased in MDD>controls
IL-1a/b, IL-2, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-18, TNFa, CRP, VEGF-C, sTNFR2
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Cytokines decreased MDD>controls
IL-4, VEGF, interferon-gamma IFG
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Markers elevated TRD>MDD
higher levels hsCRP, CRP, IL-6, TNF-α, KYN metabolites (QA, higher KYN/TRP ratio), IFN-gamma, IL-8, cortisol
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Cytokines that decrease with AD response
IL-6, TNF-a, CCL-2, IL-, TNF-a, IL-10, IL-5, GM-CSF
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Baseline markers linked to AD non response
lower IL1a, 5, ICAM-1, Higher IFN-gamma, CCL-2, IL-8, hsCRP >3mg), IL-1B, IL-6, TNF-a, neurotoxic metabolites (KYN, QA)
71
Adaptive immunity markers
IFN-y (GAMMA) IL-2, IL-4, IL-10, IL-17 Memory T cell ratios Immunoglobulin levels (IgG)- from B plasma T-cell receptors
72
Define complement
proteins that works with the immune system to help the body fight off infections and other diseases. They are a group of plasma proteins that react with each other to opsonize pathogens, induce inflammatory responses, and help eliminate foreign invaders. The complement system is a crucial part of both the innate and adaptive immune response
73
Innate response markers
IL-1b, IL-6, TNF-a Neutrophil count Complement proteins
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Monocyte
Differentiate into two phagocyte types: macrophage and dendritic cells Differentiate once exit circulation and migrate to tissue – the inflammatory cascade Can migrate to brain From bone marrow, turn into tissue macrophages
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Macrophage
Large specialized immune cells: detect, engulf (phagocytize), modulate response Long lived phagocytes Present antigens (i.e. a type of antigen presenting cell) to T-cells
76
Macrophage phenotypes
Phenotypes: M1= pro, M2=anti, Mreg= regulatory
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Central macrophages
microglia (in functional tissue-parenchyma) and border associated (at interfaces) astrocytes not macrophages but still involved in response
78
Neutrophils
Type of granulocyte WBC Short lived phagocytes Degranulates cells
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Define degranulation
Releases cell molecules needed for immune response into extracellular space
80
Dendritic cells
Initiate adaptive immune response Type of APC
81
Acute phase proteins
Proteins produced by liver during acute response EG: CRP, fibrinogen (related to clotting), serum amyloid
82
NK cells
Type of lymphocyte (of innate lymphoid cells) – part of first line of defense Innate but show characteristics of adaptive like memory and regulation of T/B cells Nonspecific killers of infected or abnormal cells Induce apoptosis and antiviral activity Secrete IFN-gamma Mobilize APCs (antigen producing cells)
83
Innate lymphoid cells (ILCs)
Type of lymphocyte Innate T-cell like cells Regulate immune response Secrete IL-4, IFN-gamma, IL-17
84
Mast cells
Sentinel cells Early cytokine response Initiate cell recruitment Secrete TNF-a, IL-1, IL-6
85
Toll-like receptors
Proteins in innate system Usually expressed on macrophages and dendritic cells PRRs - recognize PAMPS/DAMPS to activate response Linking innate/adaptive response
86
Endothelial cells
(ENDO=INNER) Specialized type of epithelium cells that lines inner surface of blood/lymph vessels – interface bloodstream ad tissues Regulate trafficking, activation of immune cells in/out of tissues Via adhesion molecule expression
87
Toll-like receptors
Proteins in innate system Usually expressed on macrophages and dendritic cells PRRs - recognize PAMPS/DAMPS to activate response Linking innate/adaptive response
88
Epithelial cells
(EPIDERMIS=OUTER) Broad term for tissue that covers and lines outer surface of organs Physical barrier between body and pathogens Activate innate response via released inflammatory mediators Can present antigens to T cells to activate adaptive
89
T cells
Derive from bone marrow stem cells Distinguish non-self-antigens from host cells Antigen specific- require activation by APCs Involved in cell-mediated response Type of lymphocyte
90
Cytotoxic T cells
CD8+ (MHC 1) Destroy infected cells
91
Helper T cells
Mediate immune response Secrete cytokines to activate B cells Th1, 2, 17
92
Th1 role
Differentiate B cells, secrete IFN-gamma
93
Th2 role
*anti inflammatory Develop IgG B-cells, recruit mast/eosinophils, secrete IL-4, IL-5, IL-13
94
Th17 role
Maintain chronic response, secrete IL-17
95
Treg cells
Suppress immune response
96
B cells
Derive from bone marrow stem cells Don’t need APC to activate Differentiate to produce specific antibodies for antigens Involved in humoral/antibody mediated response
97
Antibody-secreting B cells
From B cells Flag a pathogen for destruction when match antigen receptor Helped by Th cells and cytokines
98
Antibodies
From plasma B cells Five types: Ig A/D/E/G/M
99
Transcriptions signalling
The process by which external inflammatory signals activate specific transcription factors inside cells. These transcription factors enter the nucleus and bind DNA, regulating gene expression. - result: controls production of proteins like cytokines, chemokines, and enzymes that drive the inflammatory response.
100
Steps in transcription signalling pathway
1. Recognition of inflammatory stimuli (pathogens, cytokines) by cell surface receptors (TLRs) or cytokine receptors. 2. Activation of intracellular signaling cascades (e.g., NF-κB, MAPK, JAK-STAT pathways). 3. Translocation of activated transcription factors into the nucleus. 4. Binding to promoter regions of target genes. 5. Initiation or repression of mRNA transcription for inflammatory mediator
101
NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells)
Transcription factor Central regulator of inflammation. Controls genes for pro-inflammatory cytokines (IL-6, TNF-α), adhesion molecules, enzymes (COX-2). Upregulated MDD-innate
102
AP-1 (Activator Protein-1)
Transcription factor Regulates genes involved in inflammation and cell proliferation.
103
STAT family (Signal Transducers and Activators of Transcription):
Transcription factor Activated by cytokines via JAK-STAT (Janus kinase) pathway. Controls immune cell differentiation and cytokine production. Upregulated MDD-innate
104
IRFs (Interferon Regulatory Factors)
Transcription factor Important in antiviral responses and type I interferon production.
105
Transcription signalling in inflammation
translates extracellular signals into gene expression changes via transcription factors like NF-κB, leading to production of molecules that mediate and amplify the inflammatory response Result: Increased production of pro-inflammatory cytokines and chemokines. Amplification of the immune response. Recruitment of immune cells to sites of injury or infection. Can lead to chronic inflammation if regulation fails
106
Afferent inflammatory pathway
immune signals (like cytokines) can activate the vagus nerve, which transmits these signals to the brain, particularly affecting areas that regulate mood. This leads to the activation of microglia (brain immune cells), promoting neuroinflammation. Sympathetic nervous system (SNS)can also increase inflammation, further contributing to neuroinflammation and disrupting neurotransmitter systems like serotonin and dopamine, which are crucial for mood regulation.
107
Gut brain axis
bidirectional communication system linking the gut and brain through the nervous system, immune system, and gut microbiota
108
Gut brain axis in inflammation
When gut microbiome disrupted (dysbiosis), leads to increased gut inflammation and permeability, allowing substances to enter the bloodstream. substances, including cytokines, can travel to the brain, triggering neuroinflammation
109
How is minocycline antioxidant
Antagonizes NMDA receptors thus down regulating glutamate and excitatoxcury and nitric oxide species
110
How is minocycline neuroprotective
Inhibits apoptotic enzymes (capase), attenuates inflammation bc interferes with signalling pathways that activate microglia, restores leaky BBB
4. Thesis
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