BIOCHEMISTRY B

FAR EASTERN UNIVERSITY – NICANOR REYES MEDICAL FOUNDATION

FINALS CONFERENCE TOPICS

Compiled by: Ascaris from Sec 1-C

LIVER CIRRHOSIS
From Effort Never Dies and Danaerys Targaryen
and NADP+. CYP2E1 does its work in the microsomes of the
 Liver Cirrhosis is a clinical condition in which scar tissue cell. This is sometimes referred to as MEOS (Microsomal
replaces normal, healthy liver tissue. As the scar tissues Ethanol Oxidizing System).
replace the normal liver tissue, it blocks the flow of blood  Catalase is found in tiny organs inside of cells called
through the organ and prevents the liver from functioning peroxisomes. Catalase is found all over the human body.
properly. When catalase turns alcohol into acetaldehyde, the
 Cirrhosis rarely causes signs and symptoms in its early hydrogen which is released is bound to hydrogen peroxide
stages, but as liver function deteriorates, the signs and molecules which then becomes water.
symptoms appear, including fatigue, nausea, unintended
weight loss, jaundice, bleeding from the gastrointestinal AFFECTED PATHWAYS AND THE ACCUMULATED
tract, intense itching, and swelling in the legs and METABOLITES
abdomen.
 Hepatitis C, fatty liver, and alcohol abuse are the most
common causes of cirrhosis of the liver in the U.S., but
anything that damages the liver can cause cirrhosis,
including:
o Fatty liver associated with obesity and diabetes
o Chronic viral infections of the liver (hepatitis types B,
C, and D;Hepatitis D is extremely rare)
o Blockage of the bile duct
o Repeated bouts of heart failure with fluid backing up
into the liver

METABOLISM

1. Pyruvic Acid to Lactic Acid

Pyruvic Acid + NADH + H+ → Lactic Acid + NADH+
 This pathway is inhibited by low concentrations of
pyruvic acid, since it has been converted to lactic
acid. The final result may be acidosis from lactic
acid build-up and hypoglycaemia from lack of
glucose synthesis.
2. Synthesis of Lipids
 Excess NADH may be used as a reducing agent in
two pathways: one to synthesize glycerol (from a
glycolysis intermediate) and the other to
synthesis fatty acids. As a result, heavy drinkers
may initially be overweight.
3. Electron Transport Chain
 Ethanol→ Acetaldehyde (Alcohol dehydrogenase/ADH;  The NADH may be used directly in the electron
cytosol) transport chain to synthesize ATP as a source of
 Acetaldehyde→ Acetate (Aldehyde dehydrogenase/ ADH2; energy. This reaction has the direct effect of
mitochondria) inhibiting the normal oxidation of fats in the fatty
 Enzyme Cytochrome P450 2E1 (CYP2E1) becomes active in acid spiral and citric acid cycle. Fats may
metabolizing alcohol in chronic heavy drinkers. CYP2E1 accumulate or acetyl CoA may accumulate with
does its work in the liver. The hydrogen released by this the resulting production of ketone bodies.
reaction is bound to oxygen and to NADPH to form water
Inebriation after alcohol ingestion MANAGEMENT OF HEPATIC ENCEPHALOPATHY
 Alcohol interferes with communication between  Non-absorbable dissacharides
nerve cells and all other cells, suppressing the  Anti-biotics
activities of excitatory nerve pathways and increasing  Altering gut flora
the activities of inhibitory nerve pathways.  Increasing ammonia metabolism
 GABA- major inhibitory neurotransmitter in the brain.  Zinc Supplementation
Alcohol acts primarily at the GABA receptor to  Flumazenil
facilitate its action, thus in essence creating enhanced  Dopamine agonists
inhibition.
 Glutamate major excitatory neurotransmitter in the DEMENTIA
brain. Alcohol acts to inhibit a subset (N-methyl-D- From Uy, Miguel, Velasquez, Sugay, Arabejo, Vitug, Lim
aspartate,NMDA) of glutamate receptors thus m.,Lim i., Naval, Pereña
diminishing the excitatory actions of glutamate. Dementia
 serious loss of global cognitive ability in a previously
Wernicke-karsakoff encephalopathy in relation to chronic unimpaired person, beyond what might be expected
alcohol drinkers from normal aging.
 Wernicke-Korsakoff syndrome is a brain disorder  not a specific disease: symptoms associated with a
involving loss of specific brain functions caused by a decline in memory or other thinking skills severe
thiamine deficiency. enough to reduce a person's ability to perform
 Chronic alcoholics are at risk of developing it because everyday activities
of reduced thiamine that can interfere in many cellular  most cases are progressive
functions leading to serious brain disorders
Clinical Manifestations:
Fatty liver  Memory
 Fatty liver is caused by a combination of impaired fatty  Communication and language
acid exidation and increased lipogenesis, which is  Ability to focus and pay attention
thought to be due to changes in the [NADH]/[NAD+]  Reasoning and judgment
redox potential in the liver.  Visual perception
 At least two of these core mental functions must be
Liver cirrhosis
significantly impaired to be considered dementia.
 Microsomal enzyme oxidation system (MEOS)
pathway Types:
 Inflammation incited by acetaldehyde 1. Alzheimer's disease
 Chronic alcohol exposure also activates hepatic  most common type; accounts for an estimated 60 to
macrophages 80% of cases.
 Relationship between blood and liver cells is 2. Vascular dementia
destroyed  “multi-infarct” or “post-stroke dementia”
 Disturbed relationship between the liver cells and the  second most common cause of dementia after
channels through which bile flows Alzheimer's disease
 caused by brain injuries such as microscopic bleeding
Metabolic pathways affected in liver cirrhosis and blood vessel blockage
 Carbohydrate metab  *Location of the brain injury determines how the
 Protein metab individual's thinking and physical functioning are
 Lipid metab affected.
3.Dementia with Lewy bodies (DLB)
Clinical manifestation of liver cirrhosis are edema, ascites, bruise  accounts for about 10% of cases.
formation, portal hypertension, splenomegaly, jaundice,  caused by tiny spherical protein deposits called alpha-
gallstones, hyperesterinism, sensitivity to drugs and hepatic synuclein.
coma.
 patients of this type often have memory loss and
thinking problems common in Alzheimer's
Development of Hepatic Coma:
4. Mixed dementia
 Decreased hepatic function
 characterized by the hallmark abnormalities of more
 Decreased urea synthesis than one type of dementia —most commonly,
 Accumulation of NH3 in blood Alzheimer's and vascular dementia, but also other
 NH3 escapes hepatic detoxification types, such as dementia with Lewy bodies.
 NH3 in systemic circulation
 Brain

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5. Parkinson's disease  (APOE-e4)
 often results in a progressive dementia similar to o one of three common forms of the APOE gene
dementia with Lewy bodies or Alzheimer's. associated with a higher risk of Alzheimer's.
6. Frontotemporal dementia  Head trauma
 occur at a younger age than does Alzheimer's disease o when it occurs repeatedly or involves loss of
(ages 40-70) consciousness.
 degeneration of nerve cells in the frontal and  Heart-head connection
temporal lobes of the brain o risk of developing Alzheimer’s appears to be
increased by many conditions that damage the
NORMAL AGING vs. DEMENTIA heart or blood vessels(e.g high blood pressure,
Normal Aging Dementia heart disease, stroke, diabetes and high
Independence in daily activities Person becomes critically cholesterol)
preserved dependent on others for key  Down Syndrome
independent-living activities o causes mental retardation and characteristic
Recent memory for important Notable decline in memory for body and facial features
events, affairs; conversations recent events and ability to o people with Down Syndrome generally develop
not impaired converse AD at ages 30-50
You are worried about your Your relatives are worried o studies suggest that individuals who have a family
memory but your relatives are about your memory, but you history of Down Syndrome have a higher risk of
not are not aware of any problems developing AD.
Occasional word-finding Frequent word-finding pauses
difficulties and substitutions ETIOLOGY:
Does not get lost in familiar Gets lost in familiar territory  Cholinergic Hypothesis
territory; may have to pause while walking or o It proposes that AD is caused by reduced
momentarily to remember way driving; may take hours to synthesis of the neurotransmitter
eventually return home acetylcholine.
Maintains prior level of Exhibits loss of interest in social  Amyloid Hypothesis
interpersonal social skills activities; exhibits socially o The amyloid hypothesis postulated that
inappropriate behaviors overproduction of beta-amyloid (βA) is the
Normal performance on mental Abnormal performance on fundamental cause of the disease. There is a
status mental status fault with the processing of amyloid precursor
examinations, taking education examination not accounted for protein (APP) in the brain that leads to the
and culture into by education or production of a short fragment of APP known
account cultural factors as beta-amyloid. The accumulated clumps of
beta amyloid are known as amyloid plaques.
ALZHEIMER’S DISEASE  Tau Hypothesis
 progressive and fatal neurodegenerative disorder that o The tau hypothesis is the idea that tau
results in impairment of the person's ability to protein abnormalities initiate the disease
perform activities of daily living, as well as a variety of cascade. In this model, hyperphosphorylated
neuropsychiatric symptoms and behavioral tau when paired with other threads of tau
disturbances in the later stages of the disease eventually will form neurofibrillary tangles
inside nerve cell bodies. When this occurs,
RISK FACTORS the microtubules disintegrate, collapsing the
 Age neuron's transport system.
o the likelihood of developing Alzheimer’s doubles
about every five years after age 65. After age 85, STRUCTURAL CHANGES IN THE BRAIN:
the risk reaches nearly 50 percent.  AD affects areas of the brain involved in learning
 Family history and memory including the hippocampus,
o immediate family member with Alzheimer’s are amygdala, and areas of the temporal, frontal, and
more likely to develop the disease. parietal lobes.
 Genetic  AD is clinically diagnosed by progressive memory
o (Risk genes) increase the likelihood of developing impairment and reduced size of the hippocampus,
a disease, but do not guarantee it will happen. temporal, and frontal lobes. An MRI is usually used
 APOE to detect the changes in size.
o gene with the greatest known influence on the
risk of developing late onset Alzheimer's disease
o Found on chromosome 19 and comes in three
forms: APOE ε2, APOE ε3, APOE ε4

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AMYLOID PLAQUES & NEURO FIBRILLARY TANGLES:
 The hallmarks of Alzheimer's disease are the
accumulation of amyloid plaques between nerve
cells and neurofibrillary tangles found inside the
neurons in the brain.
 Amyloid precursor protein (APP) is an integral
membrane protein whose role is in synaptic
formation and repair; its expression is
upregulated during neuronal differentiation and
after neural injury.
 APP may be processed via a non-amyloidogenic
pathway that prevents Aβ formation or an
amyloidogenic pathway that generates Aβ.
 In the normal state, APP is initially cleaved by α-
secretase to generate sAPPα and a C83 carboxy-
terminal fragment.In the disease state, APP is
cleaved sequentially by -site APP cleaving enzyme
1 (BACE1 or β-secretase and followed by γ-
secretase. Cleavage of APP by BACE1 releases the
extracellular secreted APP β (sAPPβ) fragment
which is thought to serve as a ligand for Death
Receptor 6 and assist with axon pruning and cell
death.
 Accumulation of beta-amyloid leads to damage to
neurons, which in turn triggers inflammatory
responses causes the formation of tangles made
up of a protein called tau.
 Tau protein is a highly soluble microtubule-
associated protein (MAP). The neurofibrillary
tangles are the result of hyperphosphorylation of
the microtubule associated protein Tau.GSK-3β
and CDK5 are the kinases primarily responsible for
phosphorylation of Tau, although other kinases
such as PKC, PKA, and ERK2 are also involved.
Neurofibrillary tangles form as a result of Tau
oligomerization and lead to apoptosis of the
neuron.
NEUROTRANSMITTER INVOLVED IN AD
 Glutamate
o In AD, glutamate transporters are reduced:
o Accumulation of extracellular glutamate
o More calcium enters the post synaptic cell
causing excitatory and mitochondrial
damage (via calcium-evoked apoptosis)
 Acetylcholine
o Factors leading to decreased levels of
acetylcholine:
 Presence of Acetylcholinesterase
 Presence of Abeta at alpha7 subunit
 binding of Abeta to the alpha7 subunit of
nicotinic acetylcholine receptor (nAchr)
inhibits nAchR activity and Ach release
ASSOCIATIONS OF AD
 Association with lipoprotein and cholesterol:
o myelin sheath repair is dependent on normal
cholesterol production which in turn is
dependent on APOE
o APOE2 and APOE3-binds with and removes
Abeta
o APOE4-stabilizes Abeta in its toxic oligomeric
form
o increased cholesterol: increased risk for AD
o (Cholesterol binds with aggregated Abeta,
reducing its clearance and contributes more
to amyloid plaque)
 Association in inflammation and immune
response:
o There will be activation of inflammatory
cytokines:
o IL-1beta activation of APP synthesis, Abeta
binding proteins, and tau protein
phosphorylation which causes Neurofibrillary
tangles)
o NFalpha (apoptotic cell death)
o Abeta activates transcription factor NF-kB
(increases cytokine production)
 Association with cigarette/tobacco smoking:
o Nicotine which acts on nAchR enhances Ach
production and release.
MINI MENTAL STATE EXAMINATION
-a 30-point questionnaire test that is used to screen for
cognitive impairment.It is commonly used in medicine to
screen for dementia.
MANAGEMENT OF AD: No cure for dementia but there are
drugs that could slow the progression of AD. APP has been
the target for treatment and management since its
splitting is believed to be the major cause of AD.
CHOLINESTERASE INHIBITORS
 Tacrine tetrahydroaminoacridine or THA; hepatotoxic
 Donepzil, Rivastigmine, and Galanatamine undergoes
glucoronidation (the enzyme UDP-
glucoronyltransferase is present not only in the liver
but also in other vital organs)
 PPAR gamma AGONIST Rosiglitazone; insulin
sensitizing agent (reduces Abetain combination with
insulin)
 OTHER AGENTS:
 Gingko biloba studies showed that AD patients'
cognitive function improved after administration for
3-6 months, but is not effective for preventing AD
 DHA (docosahexanoic acid) omega-3 Fatty acid
increases transcription of tranthyretin, which is a
Abetadegrading enzyme
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 FRAGILE X SYNDROME Sherman Paradox
From Uy, Miguel, Velasquez, Sugay, Arabejo, Vitug, Lim  The risk of expressing mental retardation depends on
m.,Lim i., Naval, Pereña the position of an individual in the genogram with
Fragile-X syndrome increasing risk of manifestation in later generations.
 Second most common genetic cause of mental  As with all X-linked diseases, fragile X syndrome affects
retardation, after Down syndrome males. Analysis of several pedigrees, however, reveals
 1 in 3,600 males some patterns of transmission NOT typically
 1 in 6,000 females associated with other X-linked recessive disorders
 X-linked disorder  Resolved by analysing FMR-1 gene
 Condition is never transmitted from father to son  Pre-mutations expand into full mutation when passed
through mothers
Molecular Basis o It was the full mutation form wherein the
 Constriction in the long arm of the X chromosome characteristic clinical manifestation of fragile X
o appears that the chromosome is “broken” at this syndrome is observed
locale, it is referred to as a fragile site  The development of pre-mutations to become full
 Unusual mutation within the familial mental mutations may be related to the size of a pre-mutation
retardation-1 (FMR1) gene – gene product is fragile-X and the gender of the carrier
mental retardation protein (FMRP)  Expansion from a pre-mutation to a full mutation has
 FMRP: two important effects:
o Predominantly cytoplasmic and has a o FMR1 gene transcription is shut off
characteristic RNA-binding protein o DNA surrounding the transcriptional start site of
o Highest levels in: the FMR1 gene becomes methylated.
a. Cholinergic neurons of the nucleus basalis  Methylation occurs in a so-called CpG island,
magnocellularis a several hundred base pair segment just
b. Pyramidal neurons of the hippocampus upstream of the FMR1 transcriptional start
o Loss of FMR-1 gene function can be explained by site
two processes involved in the central dogma of
molecular biology:
1. DNA replication slippage resulting in CGG
repeat expansion
 Normal individual has a CGG repeat of 2
to 50 copies and is usually interrupted by
a single AGG
 CGG repeat is found at the 5’
unstranslated region of the gene
 CGG repeats repeats of pre-mutation
and full mutation alleles have fewer AGG
interruptions Daughter (III) of unaffected male carrier (II) was more likely to
 Few AGG interruptions CGG repeats loop have affected offspring compared to the mother (I) of the
(slippage) undergoes replication unaffected male carrier (II). They deduced that something
expansion might have changed on the X chromosome over the two
2. Methylation of CGG repeat resulting to generations. This observation became known as the, “Sherman
gene silencing Paradox”.
 Hypermethylation of the cytosine in CGG  The likelihood that an individual carrying an abnormal
repeats transcriptional silencing chromosome will manifest clinical features depends
through histone deacetylation on the number of generations through which the
 This is detected on individuals with full abnormal chromosome has been transmitted and the
mutation sex of the transmitting parent
Types of mutation
Category Number of CGG Clinical Features
repeats 1. Normal growth
Normal 5-50 2. Large head circumference
Pre-mutation 50-200 3. Long and square-shaped face
Full Mutation >200 4. Prominent forehead
5. Large ears
6. Prominent jaw
7. Macro-orchidism (abnormally large testes)
8. Delayed speech and motor development

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 9. Hyperactivity
10. Short attention span
11. Poor eye contact
12. Withdrawal response
13. Temper tantrums
14. Hand mannerisms (ex: hand-flapping)
Risk of Inheritance
 Individuals carrying the abnormal X chromosome have
a 50% chance of passing it to their offspring
 Penetrance increases with each successive generation
owing to the progressive expansion of a triplet repeat
 Expansion is dependent on maternal inheritance of
the abnormal allele; thus, daughters of normal
transmitting males are non-penetrant.
Lyonization
 Commonly known as X inactivation
 Normally, a female has 2 X chromosomes
 It is a transcriptional inactivation of one X
chromosome of a female
 This mechanism provides compensation to equalize
the level of gene expression of most X-linked genes in
females
 Results to a highly compacted, inactive chromosome
(heterochromatin)
 Occurs in early development of embryo
Other genetic disease – Trinucleotide repeats
A. Loss of Protein Function
 There is an expansions in the non-coding region
causing transcriptional silencing or down-regulation of
the associated gene
 Includes:
1. Fragile XE Syndrome
2. Friedreich Ataxia
B. RNA-Mediated Gain-of-Function Mechanism
 Expansions in the non-coding region cause toxicity and
dysfunction by affecting the following:
a) Transcriptional regulation
b) mRNA splicing and metabolism
c) RNA binding protein distribution
d) Signal transduction and cellular homeostatic
pathways.
Includes:
1. Myotonic Dystrophy
2. Fragile X-Associated Tremor ataxia Syndrome
C. Gain-of-Function Mechanism: Polyglutamine Disorders
 Polyglutamine disorder is a trinucleotide disorders
characterized by expansions in the protein coding
region resulting to an abnormal, long stretch of amino
acid in to the associated protein dominantly
inherited, gain-of-function mutation
 Disease-causing alleles: CAG (codes for glutamine)
 Includes:
1. Spinobulbar Muscular Atrophy
2. Huntington Disease
3. Spinocerebellar Ataxia
APOPTOSIS AND NECROSIS
From Uy, Miguel, Velasquez, Sugay, Arabejo, Vitug, Lim
m.,Lim i., Naval, Pereña
APOPTOSIS
 a pathway of cell death that is induced by a tightly
regulated suicide program in which cells destined to die
activate enzymes that degrade the cells' own nuclear DNA
and nuclear and cytoplasmic proteins.
 Also known as “programmed cell death” (PCD) that may be
initiated by the formation of pores in the outer
mitochondrial membrane.
Apoptotic signals
 work by preparing the cell for the death pathway by
stimulating certain regulatory proteins.
 may command the cell to either proceed with the suicidal
process or delay or completely stop it from completing
apoptosis, should the cell no longer need to die.
 The binding and subsequent initiation of apoptosis by
molecule = positive
 the active repression of apoptosis by a molecule = negative
 Withdrawal of positive signals (anti-apoptotic factors):
 growth factors for neurons
 interleukin-2 (IL-2) for the mitosis of lymphocytes.
 Receipt of negative signals (pro-apoptotic factors):
o increased levels of oxidants, UV, X-rays, and
Chemotherapeutic drugs (irreversible damage to the
DNA molecule).
o Accumulation of proteins that failed to fold properly
into their proper tertiary structure.
o Death activators (molecules that bind to specific
receptors on the cell surface and signal the cell to
begin the apoptosis program)
 tumor necrosis factor-alpha (TNF-a) that binds to
the TNF receptor
 lymphotoxin (also known as TNF-b) that also binds
to the TNF receptor
 Fas ligand (FasL), a molecule that binds to a cell-
surface receptor named Fas (also called (CD95 or
Cluster Determinant-95)
Apoptotic pathways: intrinsic vs. extrinsic
 Extracellular (extrinsic inducers): cross the plasma
membrane or undergo signal transduction to induce a
cellular response
o toxins
o hormones
o growth factors
o nitric oxide
o cytokines
 Intracellular (intrinsic inducers): initiate cell death in
response to a stress
o binding of nuclear receptors by glucocorticoids
o heat
o Radiation
o nutrient deprivation
o viral infection
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 o hypoxia
o increased cellular calcium concentration
Two main Regulatory Pathway:
 Targeting mitochondria functionality
 Directly transducing the signal via adapter proteins to
the apoptotic mechanisms
Apoptosis triggered by internal signals: The intrinsic or
mitochondrial pathway
 In a healthy cell, the outer membranes of its
mitochondria display the protein Bcl-2 (inhibits
apoptosis)
 Internal damage to the cell causes a related protein,
Bax, to migrate to the surface of the mitochondrion
where it inhibits the protective effect of Bcl-2 and
inserts itself into the outer mitochondrial membrane
by creating holes in it and causing cytochrome C to
leak out.
o Cytochrome C also serves to regulate apoptosis
by preceding morphological change associated
with apoptosis.
 Once it is released, it binds with Apaf-1 (Apoptotic
Peptidase Activating Factor 1 also known as CED4) and
ATP, which then binds to pro-caspase-9 to form an
apoptosome, a protein complex.
o Pro-caspase is cleaved by the apoptosome to its
active form (Caspase 9) activates the effector
caspase-3
o Caspases - family of proteins that are one of the
main executors of the apoptotic process. These
caspases belong to a group of enzymes known as
cysteine proteases which exist within the cell as
inactive pro-forms or zymogens, to be activated
upon cleavage following apoptosis.
 The activation of these “executioner” caspases creates
an expanding cascade of proteolytic activity which
leads to digestion of structural proteins in the
cytoplasm, degradation of chromosomal DNA and
phagocytosis of the cell
Apoptosis triggered by external signals: the extrinsic or death
receptor pathway
 Fas and TNF-receptor are integral membrane proteins
with their receptor domains exposed at the surface of
the cell.
 Binding of the complementary death activator (FasL
and TNF, respectively) transmits a signal to the
cytoplasm that leads to activation of caspase-8.
o Caspase-8 (like caspase-9) initiates a cascade of
caspase activation leading to phagocytosis of the
cell.
 When cytotoxic T-cells recognize and bind to their
target, they produce more FasL at their surface. This
binds with the Fas on the surface of the target cell
leading to its death by apoptosis.
Role of Apoptosis
 Embryogenesis
o The differentiation of fingers and toes in a developing
human embryo occurs because cells between the
fingers apoptose.
 Development and differentiation of Tissues
o At the start of menstruation the shedding off of tissues
in the endometrium is also through apoptosis
 AIDS
o One of the mechanisms by which T helper cells are
depleted is through apoptosis
o HIV enzymes deactivate anti-apoptotic Bcl-2
o In parallel, these HIV enzymes prompts FAS-mediated
apoptosis activates Pro-apoptotic procaspase-8 which
activates the extrinsic (death receptor -initiated)
pathway of apoptosis
o HIV proteins decreases the amount of CD4
glycoprotein marker present on the cell membrane
o Released viral particles and proteins present in
extracellular fluid are able to induce apoptosis in
nearby T helper cells
o HIV decreases the production of molecules involved in
marking the cell for apoptosis, giving the virus time to
replicate and continue releasing apoptotic agents into
surrounding tissues.
 Cancer
o P53
 Stimulates the transcription of p21 (inhibits cyclin
cdk complexes) and GADD a dna repair enzyme
 If dna repair was not successful it activates BAX
gene and IGF-BP3
o Li-Fraumeni Syndrome
 An inheritance of a mutation in the p53 gene
o Follicular lymphoma and chronic myelogenous
leukemia
 Over expression of the bcl-2
o Malignant Melanomas
 Mutation in p53, p16, cdk4
o DNA viruses SV40,papillomavirus,adenovirus
 Encode proteins that inactivate pRb and p53
o Epstein-Barr virus
 Encodes a bcl-2 that restricts apoptosis
 Immune defense
o distinguishing self from non-self
o Autoimmune Lymphoproliferative Syndrome
 rare disorder of abnormal lymphocyte survival
caused by defective Fas mediated apoptosis.
Different Laboratory indices:
 Terminal Transferase dUTP Nick end labeling (TUNEL
assay)
 DNA laddering
 Apoptosis Assays Based on Protease Activity Caspases
 Annexin A5 affinity assay
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Improve this chart Apoptosis Necrosis dependent DNA polymerases (reverse
Natural Yes No transcriptases)
Effects Beneficial (may be Detrimental 2. LAGGING STRAND FORMATION
physiological) (always  Unwinding by helicase Annealing of Primers by
pathological) primase Elongation by DNAP III Removal and
Introduction Apoptosis Necrosis is the Replacement of Primase by DNAPI Ligase activity
programmed cell premature death of  But sinc among nucleotides, removal of the primer at
death (PCD) in cells and living the 5’ end of the laggings strand leaves no OH, thus
humans & tissue. It is caused inability of replacing the primers with DNA nucleotides
multicellular by external factors, by DNAP I 3’ overhang (shortening of the lagging
organisms. PCD such as infection, strand)
involves a series of toxins or trauma. 3. CELLULAR SENESCENCE
biochemical events This is in contrast
leading to a cell to apoptosis, which
destruction and is a naturally
death. occurring cause of
cellular death.
result Can prevent tumor Necrosis results in
formation inflammation,
(homeostasis which could
between cell death become chronic.
rate and mitosis
rate)
definition programmed cell the cell or tissue  denotes a stable and long-term loss of proliferative
death damage due to capacity, despite continued viability and metabolic
external factors. activity disrupting metabolism resulting in
process Membrane membrane deterioration and death.
blebbing disruption  The finite lifetime of diploid cell strains in vitro may be
shrinkage of cell respiratory poisons an expression of aging or senescence at the cellular
nuclear collapse and hypoxia which level.” (HAYFLICK)
(nuclear cause ATP  PHASES
fragmentation, depletion, o Phase I
chromatin metabolic collapse,  period of little proliferation
condensation, cell swelling and  culture establishes and covers the surface of
chromosomal DNA rupture leading to the culture flask
fragmentation) inflammation o Phase II
apoptotic body  rapid cell proliferation
formation  cells divide in culture
engulfment by o Phase III
white blood cells  cells start dividing slower
 proliferation gradually proceeds a complete
TELOMERASE, AGING, AND CANCER halt
From Uy, Miguel, Velasquez, Sugay, Arabejo, Vitug, Lim  Involves Replicative senescence
m.,Lim i., Naval, Pereña  HAYFLICK LIMIT
o Limit of cellular replicative capacity
1. PHYSICAL STRUCTURE OF CHROMOSOME o Telomeres progressively shortened causing cells
 Can be linear (nucleus of eukaryotes) or circular to reach hayflick limit
(prokaryotes and mitochondrial DNA) o Telomere is too short that it can no longer divide
 Linear Chromosome: o Some cells have small cellular density due to a
o centromere (AT rich central region; essential more sensitive cell to cell inhibition (contact
locus for accurate division during mitosis and inhibition)
meiosis) o 50 cell divisions only
o Telomere (TG rich repeats ( 5’- TTAGGG- 3’)
 has protein components (telomere binding MECHANISMS OF SENESCENCE
proteins) :TRF1 , TRF2 , hRAP1, TIN2 ,  Telomeric shortening
TANK1/TNKS , TANK2/TNKS2 , and WRN  Accumulation of damage
 Telomerase: multisubunit RNA template-  Glycation (AGE)- converts arginine to ornithine
containing complex related to viral RNA –

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  Impaired adipogenic potential of senescent  Telomere Repeat Binding Factor 2- binds the single
preadipocytes is a hallmark of adipose aging and stranded DNA to double stranded DNA
aging-related adipose dysfunction
 Cross linking 6. Telomerase can elongate DNA and prevent
o Transglutaminase (tTGase) mediated senescence of cells but it can be harmful specially if it
macromolecule crosslinking of histone subunits is the cancer cell that is immortalized. Recent studies
may play a mechanistic role during aging suggest that in the future, combining the RNA
(senescence) component with the hTERT gene product they could
 Mitochondrial DNA damage – can induce cell cycle immortalize cells without turning them cancerous.
arrest (may be caused by inc. ROS levels)
o mtDNA does not have any histones or any enzyme 7. It is possible to revert “old’ cells into “young cells
repair system to protect from free radical damage again”. Experiments in animals exhibited "a near
decrease function of ETC energy crisis 'Ponce de Leon' effect" (like fountain of youth?)—that
compromised tissue functions is, other organs recuperated from degenerated state
upon activity of telomerase enzyme on somatic cells
PROPERTIES OF CELL DURING SENSCENT PHASE
 Bigger, more diverse morphology types 8. Long term aging cannot be attributed to gradual
 Some cells have small cellular density due to a more shortening of telomere alone, since there are a lot to
sensitive cell to cell inhibition (contact inhibition) consider including improvement in sanitation, the
 turn blue when exposed to a particular chemical development of antibiotics, vaccines, and modern
 lysosomes increase in number and size pharmaceutical drugs, resulting to humans living
 Aging will increase autophagy, digestion of the cell's longer
organelles
 Deletions in the mitochondrial DNA (mtDNA) 9. Inhibition of telomerase could provide a safe and
 during Replicative senescence effective way to eliminate cancers, by making
immortal cells, mortal. (telomerase in somatic cells-
 increased activity of metalloproteinases which
could be the first universal marker for cancer.)
degrade the extracellular matrix
 decreased ability to express heat shock proteins
ERECTILE DYSFUNCTION
 secretes cytokines and chemokines
From Uy, Miguel, Velasquez, Sugay, Arabejo, Vitug, Lim
 trigger a variety of cellular responses
m.,Lim i., Naval, Pereña
ERECTILE DYSFUNCTION
SENESCENCE AND CANCER
 Inability to maintain an erection of the penis
 Senescence has TUMOR SUPPRESSING
 Affects about 5% of men in their 40s and 15-25% of
mechanism,limiting the replicative potential of pre
men by the age of 65
neoplastic cell altered gene expression, growth arrest,
 Most commonly caused by reduced blood flow to the
apoptosis
penis and nerve damage
 May be oncogene induced
Erection
 Physiological phenomenon wherein the corpora
4. TELOMERASE
cavernosa of the penis becomes engorged with
 Telomere shortening leads to Telomeric DNA (single
venous blood making the penis firmer and enlarged
stranded at 3’ end; contains simple tandem repeats of
 Result of increased arterial inflow and restricted
G rich
venous outflow
 Shortening of DNA eliminates the ff functions of DNA
o Capping
Erection Ejaculation
o Recombination
Engorgement of the Ejection of semen
o End to end fusion
penis with venous from the male repro
o degradation
blood tract
 Telomerase
Involves corpora Involves
o A unique polymerase with reverse transcriptase
cavernosa bulbospongiosus
activity specialized in synthesizing multipleshort
muscle
repeats
o With 2 essential components Parasympathetic Sympathetic control
 hTR or hTERC- RNA component control
 hTERT – with reverse transcriptase activity
Erectile Dysfunction Impotence
5. Abnormal condition Abnormal condition
 Telomere Repeat Binding Factor 1- binds to telomeric associated with males associated with males
DNA sequence & females

9
Main cause is lack of Caused by various b) Psychological
blood supply to the factors like lack of 1. Emotional
penis during sexual control by penile 2. Excessive sympathetic stimulation
activity nerves, unhealthy c) Medication-related
lifestyle, diet,  antihypertensives, antidepressants, hormone
malnutrition, bending related
of penis & physical
injuries BPH medications
 Drug of choice is alpha blockers [terazosin (Hytrin)
Nitric Oxide (NO) Doxazosin (Cardura)] over 5 alpha reductase inhibitor,
 Endothelial-derived relaxing factor which can cause erectile dysfunction.
 Potent muscle relaxant
 Synthesized from Arginine and O2 by NO synthase
enzyme (NOS)
 arginine + O2 citrulline + NO

Phosphodiesterase Enzyme (PDE)

 Enzymes that catalyze the degradation of the cyclic
nucleotides, cyclic AMP and cyclic GMP, to the
corresponding 5’ nucleotide monophosphates
 Catalyze the hydrolysis of phosphodiester bonds
 Regulate the intracellular concentration of cyclic
nucleotides
PDE5
 Human phosphodiesterase 5 (PDE5): responsible for
the degradation of cGMP in the smooth muscle cells
lining the blood vessels supplying the corpus
cavernosum of the penis, which leads to erectile
dysfunction
 Found in high concentration in smooth muscle cells of
the corpora cavernosa
Risk factors
 Age group: Bet 40-70 y/o
 Medical conditions, particularly diabetes or heart
problems.
o Being overweight- risk for CVD; circulation and
vascular problems
o (hypercholesterolinemia)
o Tobacco: restricts blood flow to veins and
arteries.
o Certain medical treatments, ex. BPH
 Medications: antidepressants, antihistamines and
medications to treat high blood pressure, pain or
prostate cancer. (loss of libido)
 Psychological conditions: stress, anxiety,depression
 Drug and alcohol use: long-term
 Injuries: damage the nerves that control erections.
 Prolonged bicycling which may compress nerves and
affect blood flow to the penis, can lead to temporary
erectile dysfunction.

ED in DM

Etiology:
Causes of Erectile dysfunction :
a) Physical
1. vascular- decrease blood flow
2. neurogenic- ex. Spinal cord injuries
3. hormonal –decrease in Androgen
4. anatomical- ex. Peyronie’s dsx

10
Diabetic Neuropathies Maillard Reaction
5 types:  reaction between carbohydrates (sugar) and proteins,
1. Sensorimotor neuropathy- numbness, paresthesia and is responsible for changes in color, flavor and
2. Autonomic neuropathy- sympathetic and nutritive in food.
parasympathetic pathway  process by which a reducing sugar attaches to an
3. mono neuropathy- cranial nerve palsies (commonly in amino group of an amino acid residue and then
CN IV, VI and VII undergoes rearrangement to form a ketoamine-linked
4. entrapment neuropathy- carpal tunnel syndrome sugar.
(median nerve), ulnar compression syndrome  Amadori products have been demonstrated in
5. proximal neuropathy- proximal muscle of the lower collagen, myelin, albumin, hemoglobin, and low-
limb (buttocks, thigh, legs); painful muscle wasting density lipoproteins. In long-lived proteins,
irreversible
Autonomic Neuropathies  Steps:
 Causes ED when it affects the nerves that control 1. initial step: formation N glycoside
erection. (pudendal nerves, etc) 2. After formation of N glycoside the immonium ion
 Mechanism: is formed and then isomerize, this reaction is
o Unclear called Amadori rearrangement and forms a
o Complex interaction between nerves and blood compound called ketosamine
vessels 3. The ketosamine products then either dehydrates
o High glucose interferes w/ the ability to transmit into reductones and dehydro reductones, which
impulses are caramel, or products short chain hydrolytic
fission products such as diacetyl, acetol or
Macrovascular Microvascular pyruvaldehyde which then undergo the Strecker
complications complications degradation.
Stroke Nephropathy
Peripheral Vascular dse Retinopathy Oral Agents
Atherosclerosis Neuropathy  Sildenafil Citrate (Viagra, Revatio)
o Potent and selective inhibitor of cGMP specific
phosphodiesterase type 5 (PDE-5) which is
responsible for degradation of cGMP in the
corpus cavernosum.
 Tadalafil (Cialis)
o Work by inhibition of PDE-5 Distinguishing
pharmacologic
o feature is longer half-life (17.5 hours), longer half-
life results in a longer duration of action, and is
responsible for the nickname of the “weekend
pill”
 Apomorphine Hcl (Uprima)
o stimulates dopamine receptors in the brain.
These receptors in turn transmit excitatory signals
down the spinal cord to the sacral
parasympathetic nucleus, stimulating activity of
the sacral nerves supplying the penis.
 Yohimbine
o A purported aphrodisiac. A selective competitive
alpha-2 adrenergic receptor antagonist which is
responsible for sensing catecholamines and
telling the body to decrease its production.
 Injection therapy
Summary: o alprostadil, which increases penile blood flow
 DM causes ED by reducing blood flow to the penis, o not safe for blood thinner users
inhibiting autonomic regulation, and depleting Nitric  Inserted medications:
oxide synthase. o MUSE: is a pre-filled, single-use, plastic applicator
 2 vascular complications of DM causes ED containing a suppository of the drug alprostadil,
inserted into the urethral opening at the end of
 Autonomic neuropathy (sympa and para pathways)
the penis and let it dissolve.
 Peripheral vascular disease (vascular integrity)

11
  Vacuum Devices:
o Best tolerated by people with a moderate degree NEUROTRANSMITTER
of ED, in comparison to mild or severe  A neurotransmitter is a compound released by a nerve
dysfunction. terminal when the nerve is triggered by an electrical
 Penile Implants: impulse.
o For more serious cases of ED, surgical implants
are available.
 Surgery
o For men with damaged blood vessels, surgery can
be performed to bypass blocked arteries to the
penis, or tie off leaky veins that allow blood to
escape from the penis during an erection.

Prevention of ED:
1. Watch what you eat.
2. Maintain a healthy weight.
3. Avoid high blood pressure and high cholesterol
4. Drink alcohol in moderation or not at all
5. Exercise regularly.
6. Don't rely on Kegels. CATEGORIES OF NEUROTRANSMITTERS
7. Keep tabs on testosterone. 1. Amino acids
8. Avoid anabolic steroids.  glutamate, aspartate, glycine, serine and gamma
9. If you smoke, stop. aminobutyric acid (GABA)
10. Steer clear of risky sex. 2. Monoamines
11. Curb stress.  Dopamine, serotonin, melatonin, epinephrine
12. AVOID Drugs that can precipitate Erectile Dysfunction and norepinephrine
o Blood Pressure Medications 3. Peptides.
o Antidepressants  calcitonin, glucagon, vasopressin, oxytocin and
o Antihistamines beta-endorphin

BIOCHEMICAL BASIS OF DEPRESSION DIFFERENCE BETWEEN HORMONES AND NEUROTRANSMITTERS

From Fernandez, Chester Kyle D. Neurotransmitter Hormone
Mechanism of Through Bloodstream
INTRODUCTION release synapse
 Neurotransmitters and hormones are chemicals Secretory Vesicles in the Endocrine
secreted inside our brain and are largely responsible organs synaptic bulb glands
for our behavior and attitude.
Duration of Quick , Longer,
response and instantenous prolonged
HORMONE
effect effect
 A hormone is a compound produced by endocrine
Associated Nervous Endocrine
gland and is released directly into the bloodstream
with: System System
 Examples of Hormones
o Estrogen – menstruation and reproduction cycles
 Both are vital for human beings as they play an
o Progesterone – fertility and pregnancy
important role in many bodily processes such as
o Testosterone – energy and sexual function
digestion, metabolism, reproduction etc.
o Thyroid Hormone – metabolism
 They are also important in mood control.
o Cortisol – stress hormone
o Melatonin – sleep-wake cycle
NEUROTRANSMITTERS AND THEIR FUNCTIONS
 these hormones has something to do with depression
a) ACETYLCHOLINE
 Both excitatory and inhibitory
 Functions:
 CNS: Synaptic plasticity, learning and short term
memory, decision making
 PNS: autonomic nervous system
 It is also concerned with regulating the activities in
certain areas of the brain, which are associated with
attention, arousal and arousal.

12
  People with Alzheimer's disease are usually found to  Serotonin is an important inhibitory neurotransmitter,
have a substantially low level of acetylcholine. which has been found to have a significant effect on
emotion, mood and anxiety.
 It is also involved in regulating sleep, wakefulness and
eating.
 A significantly low serotonin level is found to be
associated with conditions like depression, suicidal
thoughts and obsessive compulsive disorder.
 Many antidepressant drugs work by affecting the level
of this neurotransmitter.

D. GAMMA AMINOBUTYRIC ACID (GABA)

 Chief inhibitory NT that slows down neuron activity in
order to prevent their over excitation
 ↓ GABA = anxiety disorders
 Responsible for regulation of muscle tone
 L- glutamine: precursor

B. DOPAMINE
 mono amine + precursor L DOPA
 cannot cross the BBB
 Precursor to Epi and NE
 Functions:
 Reward-driven learning
 Behavior, cognition, voluntary mov’t, motivation,
sleep, mood, attention and appetite E. GLUTAMATE
 present chiefly:  Glutamate is an excitatory neurotransmitter.
o Ventral tegmental area  It is the most commonly found neurotransmitter in the
o Substantia Nigra Pars compacta central nervous system.
o Arcuate Nucleus  Glutamate is mainly related with functions like
 Drugs like cocaine, heroin, nicotine, opium and even learning and memory.
alcohol increase the level of this neurotransmitter, for  An excessive glutamate production may be related
which the user of such drugs feels good. with the disease, known as amyotrophic lateral
 Decreased level of dopamine is associated with sclerosis (ALS) or Lou Gehrig's disease.
Parkinson's disease
 Patients of schizophrenia are usually found to have F. EPINEPHRINE AND NOREPINEPHRINE
excess dopamine in the frontal lobes of the brain.  Epinephrine is an excitatory neurotransmitter, that is
derived from norepinephrine.
C. SEROTONIN  Epinephrine controls mental focus and attention.

13
  Norepinephrine is also an excitatory neurotransmitter DEGRADATION OF SEROTONIN
and it regulates mood and both physical and mental
arousal.
 Increased secretion of norepinephrine raises the heart
rate and blood pressure.

G. ENDORPHINS
 Endorphins are the neurotransmitters that resemble
the opioid compounds like opium, morphine and
heroin in structure.
 Like opioids, endorphins can reduce pain, stress and
promote calmness and serenity.
 These are the neurotransmitters that enable some
animals to hibernate by slowing down metabolism,
respiration and heart rate.

BIOCHEMICAL MECHANISM OF DEPRESSION

Uptake:
Monoamine transporter:
(SERT) – Serotonin transporter
- presynaptic terminal

Lowered mood occurs when the brain cannot access enough of

the right combinations of these neurotransmitters.

BIOSYNTHESIS OF SEROTONIN

14
BIOSYNTHESIS OF DOPAMINE BIOSYNTHESIS OF NE AND E
Synthesized mainly by neuronal tissues and medulla of Adrenal
gland
Precursor of NE

DEGRADATION OF DOPAMINE DEGRADATION OF NE AND E

THEORIES OF DEPRESSION
A. BIOGENIC AMINE HYPOTHESIS
- “depression is caused by a deficiency of monoamines,
particularly noradrenaline and serotonin”

15
 Histaminergic receptor blockade:
- Sedation
- weight gain,
- Hypotension

Muscarinic receptor blockade:

- blurred vision
- dry mouth
- Constipation
- urinary retention
- Confusion
- delirium

C. SEROTONIN-ONLY HYPOTHESIS
- emphasizes the role of serotonin in depression and downplays
noradrenaline
- introduction of SSRI (selective serotonin re uptake inhibitor)

B. RECEPTOR SENSITIVITY HYPOTHESIS

- “depression is the result of a pathological alteration
(supersensitivity & up-regulation) in receptor sites, which
results from too little stimulation by monoamines,”

Shortcoming of the hypothesis:

TCA’s are non-selective: they also block postsynaptic receptor
sites, including cholinergic (muscarinic), histaminergic, and
adrenergic receptor sites.
 it does not explain why there is a delay in onset of
clinical relief;
 it does not explain the role of noradrenaline in
depression.
D. PERMISSIVE HYPOTHESIS
 “ the control of emotional behavior results from a
balance between noradrenaline and serotonin.”
 both the manic phase and the depressive phase of
bipolar disorder are characterized by low central
serotonin function

16
  rise of SNRIs – re uptake of both serotonin and
noradrenaline MEDICAL CONDITIONS
 Cardiovascular disease
 ↓serotonin ↑ noradrenaline  Stroke
 Manic disorder  Diabetes
 Cancer
E. NEUROENDOCRINE HYPOTHESIS  Hormonal disorders
 “ pathological mood states are explained or  Thyroidism
contributed to by altered endocrine function.”  Perimenopause
↑Cortisol  Parkinson’s and Alzheimer’s disease
↓Estrogen, Progesterone, Testosterone, Thyroid, Melatonin
RISK FACTORS OF CLINICAL DEPRESSION
CLINICAL DEPRESSION In adults
DEPRESSION  Female sex
 Depression is a serious illness that can take a terrible  Marital status
toll on individuals and families.  Advanced Age
 Untreated depression can result in emotional,  Previous episode
behavioural and health problems that affect every  Heredity
area of your life.  Lower socioeconomic status
TYPES OF DEPRESSION  Chronic (long-term) medical condition
1. Major Depressive Disorder
 Underlying emotional or personality disorder
 impairs a person's ability to work, sleep, eat, and
 Substance abuse
function as he or she normally would
2. Dysthymic Disorder
In Children/ Teenage years
 milder yet more enduring type of major depression
 Gender: Female
3. Bipolar Disorder
 Continual mental or emotional stress, at home or at school
4. also known as manic-depression or manic-depressive
 The presence of any medical condition, even as mild as
disorder; mood that alternates
acne
5. Cyclothymic Disorder
 A recent loss
 a milder yet more enduring type of bipolar disorder
 Attention problems (ADHD), learning, or conduct disorder
CAUSES OF DEPRESSION  Obesity
 It is not fully known what exactly causes clinical
GENETICS OF DEPRESSION
depression for a particular individual.
 What appears to be inherited is a vulnerability to
 The following are a list of some factors that influence
depression.
a person to develop the said clinical condition:
 However, it does not mean that we are destined to become
BIOCHEMICAL FACTORS depressed.
 Chemical imbalances in the brain  If a parent or sibling that has had major depression,
another member of the family may be 1.5 to 3 times more
 Alterations in the functioning of neurotransmitters
likely to develop the condition than those who do not have
 Abnormal levels of serotonin, noepinephrine and
a close relative with the condition.
dopamine
 Inheritance of a biological vulnerability to develop
MEDICAL CONDITIONS
depression
 Depression may be caused or precipitated by a known or
 Environmental Factors
unknown physical medical condition.
 academic and/or work demands
 Substance-Induced Mood Disorder
 balancing school, family, work and social life
 Seasonal Affective Disorder (SAD)
 financial difficulties
 Postpartum Depression
 peer pressure
 Premenstrual Dysphoric Disorder
PSYCHOLOGICAL TENDENCIES
OTHER MEDICAL CONDITIONS:
 pessimism
 Symptoms of depression may also signify the presence of
 insecurities
a medical condition, which once treated may alleviate the
 self-esteem/ self-confidence issues depressive symptoms.
 Alcohol or Drug Intake  Epilepsy
 May be a cause or effect of depression  Diabetes
 Aggravates the condition  Hypothyroidism

17
 Hyperthyroidism
 Hypoparathyroidism
 Hyperparathyroidism
 Multiple Sclerosis
 Stroke
 Brain Trauma
 Porphyria
 Wilson's disease
 Lyme Disease
 Syphilis
 Pellagra
 Hungtington’s
 Parkinson’s
 Pancreatic Cancer

PHARMACOLOGIC THERAPY FOR DEPRESSION

 Selective serotonin reuptake inhibitors
 Selective serotonin/norepinephrine reuptake inhibitors
(SNRIs)
 Atypical antidepressants
 Tricyclic antidepressants
 Monoamine oxidase inhibitors (MAOIs)
 St. John's wort

THERAPEUTIC MANAGEMENT FOR DEPRESSIONS

 Psychotherapy
 Cognitive-behavioral therapy
 Interpersonal therapy
 Hospitalization

OTHER HORMONES/ NEUROTRANSMITTERS IMBALANCES

 Estrogen
 Endorphins
 Oxytocin
 Enkephalins
 Phenylethylamine

18