IB 435 Herbal Remedies Exam 2

Development of first antibiotic

- 1928: discovered that penicillium mold generates a substance that kills bacteria

- 1941: purify penicillin and develop the process to produce it at scale

Antibiotics

- Drugs that block the growth and reproduction of bacteria

- primarily derived from bacteria, plants and fungi

Why do bacteria produce antibiotics? Hypothesis 1

Microbes produce antibiotics to gain a selective advantage against competing microbes (allelopathy)

Why do bacteria produce antibiotics? Hypothesis 2

microbes may produce antibiotics to alter transcriptional profiles of target bacteria, and thus they may act as signaling molecules

Swarming

multicellular surface movement via flagella

Swimming

individual movement in liquid via flagella

Twitching

Surface of movement via movement of pili

Gliding

active surface movement without flagella or pili

Sliding

passive surface translocation via growth

Biofilms

- bacterial colonies attached to a surface

- responsible for more than 3/4 of bacterial infections

- formation depends on production of extracellular matrix

- energetically costly

- increased resistance against environmental stress factors, host immune defenses and antibiotics

Biofilm formation

1) Substratum preconditioning by ambient molecules

2) attachment of planktonic bacteria

3) Cell-cell adhesion: Cell to cell signalling and exopolymer production

4) Proliferation: diffusions of O2 and nutrients through biofilm

5. Maturation: secretion of polysaccharide matrix

6. Dispersion: detachment of planktonic bacteria

Quorum-sensing signals

- influence biofilm formation

- assessment of population density

- regulates bacterial gene expression. in response to density

5 targets for antibiotic use

- cell wall

- plasma membrane

- ribosome

- DNA/RNA synthesis

- Metabolic pathways

problems with antibiotics

- expensive and timely to develop

- antibiotic resistance

Cause of antibiotic resistance

- overuse for treatment

- incomplete course of medication

- overuse in agriculture

- poor infection control in hospital

- poor hygiene and sanitation

- failure to identify new therapeutic agents

Bacterial resistance mecahnisms

- increased efflux

- decreases influx

- target site alteration

- target amplification

- antibiotic inactivation

how to combat antibiotic resistance

- new synthetic antibiotic to fight drug-resistant superbugs

- new antibiotics created

- look back at natural systems and products

How does this new strategy of anti-virulence work?

- identifies compounds that are not themselves antibacterial but that restore activity of existing antibiotics

Antibiotic adjuvants

nonantibiotic compounds that enhance antibiotic activity either by blocking resistance or by boosting the host response to infection.

Type 1 adjuvants

- work directly on bacteria

- inhibit enzymes or circumventing intrinsic resistance via efflux pumps or antibiotic entry

Type 2 adjuvants

- increase host antimicrobial capacity

Anti-virulence agents from nature

- hamamelitannin --> disrupts staph quorum sensing

- phloretin --> counteracts c.diff toxins

- flavones and sapogenins --> block quorum sensing in MRSA

How determine if a systematic review/meta-analyses is good?

- large number of reliable studies cited

- freedom from bias as key criteria

- peer-review

- follow accepted methods of selecting papers

How to write a good systematic review or meta-analysis?

- thoughtful research question

- thoughtful search terms

- use PICO

- find all possible resources

human variation and xenobiotics

- xenobiotics: foreign substances

humans react differently to foreign substances

- variation has led to an increase in personalized medicine to match treatments to peoples genotypes

- makes it difficult to know if a medicine or treatment will work

Bitter taste receptors

- adapted to protect us from toxic substances

- prefer sweet, avert from bitter as babies

- variation in the level of bitterness someone can taste --> based on a genotype

Cilantro

- varied taste across humans

- some enjoy the taste and others think it taste like soap

Miraculin (miracle berry)

- a type of protein extracted from the 'miracle berry' which alters taste perception in humans

- binds to hT1R2-hT1R3 receptor as an antagonist at neutral pH but at acidic it becomes an agonist

Parasitism

- A relationship between two organisms of different species where one benefits and the other is harmed

- infectious agent must be transmissible between hosts

Endoparasites

- live inside the host

- ex: prions, viruses, bacteria, fungi, protozoans, trematodes, nematodes, and cestodes

Ectoparasites

- live on the body

- ex: ticks, mites, fleas, mosquitoes, and sand flies.

cause of the increase in spread of vector-borne diseases

- commerce

- poverty

Sandflies

spread leishmaniasis ( second biggest parasitic killer)

Ticks

spread lyme disease, rocky mountain spotted fever and alpha-gal syndrome

Fleas

- transmit plague bacterium

- causes 3 plagues

Vector species common features

- complex transmission cycle

- high turnover in animal reservoirs (temporary herd immunity)

- human immunity not important it transmission cycle

Mosquito- borne challenges

- amplifies quickly

- influenced by factors not easily measured/predicted far in advance

- Stochastic process subject to substantial random variability

Tick-borne challenges

- amplifies slowly

- more predictable

- long term trends garner less public attention

Strategies to address arthropod vector diseases

- vaccines

-reducing the number of bites

- physical barriers

- alter environment

- pesticides

- repellents

Challenges with vaccines

- long development times ( new tech mRNA vaccines might overcome this)

- expensive to produce

- challenging to distribute

- may have different efficacies for different strains

Pros of pesticieds

- effective at quickly reducing population numbers

- provide some level of residual impact

- relatively inexpensive and easier to distribute than vaccines

Cons of pesticides

- evolution of resistance

- unintended environmental effects

- sometimes challenging to reach critical life stages for treatment

Pros of repellents

- Less selective pressure = less likely to observe resistance evolve?

- More targeted spatially (applying directly to area of need rather than broadly)

- Prevents bites. No bites = no disease transmission.

- May work on several vectors simultaneously

Cons of repellents

- Effects are not long-lasting (low residual power).

Doesn't kill.

- R&D has been a lot of trial and error, so we don't have a ton at our disposal right now. - We have to be around it, so smell and skin-feel is important.

Historical use of repellents

- first discovered using trial and error

- first used to repel flies

- castor oil used to protect fisherman against biting insects

Citronella

- natural remedy to repel mosquitos

- composition varies within species, season, and environmental conditions

DEET

- a chemical that is widely used in insect repellents

- highly effective against mosquitos

Problems with DEET

- adverse reactions

- offensive odor

- oily skin feel

- perception that DEET is an environmental hzard

Pharmacophore

set of features that is common to a series of active molecules

what type of information can investigators obtain through in silico modeling

- 3D structure

- Chemical and physical structure - Structural comparisons between molecules

Graphical visualization of complexes between target molecules and other molecules

Predicting the match between modeled molecules and related molecules, and using that information to predict potency

biorational design

helped with the discovery of repellents

- inspired from nature "chemical anointing

Modes of action on insect repellents

activation or inhibition of olfactory/odorant receptors

1. Fixative effect of DEET on the attractant, octenol.

2. Interaction of citronellal with a receptor assemblage through an allosteric site on Drosophila Orco.

3. Activation of a mosquito TRPA1 channel by citronellal

4. Activation of OR8-Orco by interaction of octenol with the orthosteric site on OR8.

5. Inhibition of octenol response by interaction of DEET with an allosteric site on OR8.

6. Activation of OR2-Orco by interaction of indole with the orthosteric site on OR2. G.

7. Activation of OR2-Orco by interaction of DEET with the orthosteric site on OR2.

hypertension

chronic high blood pressure

Blood pressure

- force of blood pushing against the artery walls

- measured systolic/diastolic

Systolic blood pressure

pressure causes when the heart pumps blood in the arteries

Diastolic pressure

pressure between beats

Blood pressure regulation

regulated by changing heart output --> heart rate and stroke volume

Blood flow resistance

- Opposition to blood flow in vessels

- caused by the changing of the diameter of vessels (vasodilation and vasoconstriction

Primary hypertension

- no known causes

- 90% of cases

Secondary hypertension

- attributed to a diagnosable disease/condition

Organs involved in blood pressure regulation

- heart

- brain

- kidney

- liver

-lungs

sympathetic cardiac nerves

stimulate cardiac output by increasing heart rate and contractility

parasympathetic vagus nerve

reduce cardiac output by reducing heart rate

Atrial natriuretic peptide (ANP)

- secreted by atria

- lowers blood pressure by causing vasodilation and by stimulating kidneys to excrete more water and Na+

- lowers blood pressure by reducing blood volume

Nitric oxide (NO)

- signaling molecule secreted by cells in blood vessels

- causes vasodilation

brain and blood pressure regulation

- vasomotor center in medulla regulates blood vessel diameter

- cardiovascular center signaled when conditions require blood pressure changes

aortic and carotid chemoreceptors

detect CO2 and O2 levels in the brain

Aortic and carotid sinus baroreceptor reflexes

pressure receptors in brain

antidiuretic hormone (ADH)

- produced by the hypothalamus and released by the pituitary gland

- raises blood pressure by stimulating kidney water retention

Kidney, liver and lungs and blood pressure regulation

- manage blood volume via hormone secretion

- Adrenal medulla secretes epinephrine and norepinephrine

- When blood pressure drops the renin-angiotensin systems kicks in

renin-angiotensin system

- kidneys secrete renin which converts angiotensinogen to angiotensin I

- lungs secrete Angiotensin-Converting Enzyme (ACE) to convert angiotensin I to angiotensin II

- angiotensin II stimulates release of of aldosterone from adrenal gland

Angiotensin II

- constricts blood vessels

- reduces blood volume delivered to kidneys and its ability to excrete

- stimulates release of aldosterone

Aldosterone

- secreted from the adrenal gland

- reduces urine output by increasing water and Na+ retention

Evolution of hypertension

- may be a maladaptation to low salt conditions

- observed that too much salt led to pulse hardening

- wasn't a disease until people found ways to measure blood pressure

- took time to determine "normal" blood pressure

Process of discovering how to measure blood pressure

- recorded intra-arterial blood pressure by inserting glass tube into horse artery

- developed sphygmograph

- mercury sphygmograph invented

- technology brought to the US

- auscultation (listening with stethoscope) rather than palpation

5 ways to treat hypertension

- diuretics

- ACE inhibitors

- alpha blockers/alpha-adrenergic antagonists

- beta blockers

- calcium channel blockers

Diuretics

- reduce sodium uptake and increases urine excretion by the kidney

- ex: hydrochlorothiazide, parsley

ACE (angiotension-converting-enzyme) inhibitor

- inhibit the conversion of angiotensin I (ATI) to angiotensin II (ATII), blocking aldosterone releases therefore allowing sodium ion excretion

- ex: lisinopril, Rauvolfia, tumeric

Alpha blockers/alpha-adrenergic antagonists

- prevents norepinephrine from causing muscle contraction in walls of small blood vessels

- ex: prazosin/Minipress, saw palmetto, ginseng, Ligusticum wallichii, Chuan Xiong: tetramethylpyrazine

Beta blockers

- competitive antagonists of norepinephrine and epinephrine beta receptors on nerve cells

- slows SA node which initiates heartbeats

- dilates arteries

- ex: propranolol, hawthorn, garlic

Calcium channel blockers

- rate control drugs that block signals to SA node by interfering with calcium ion entry to muscle cells

- ex: Tetrandrine, Stephania tetrandra(Feng Fan Ji, Chinese herb), butyl phthalide (Apium graveolens = celery)

Atherosclerosis

- Buildup of plaque in arteries

- begins with injury to inner artery wall

- LDL in endothelium are oxidized and generate free radicals causing inflammation

- Monocytes adhere to endothelium and penetrate the arterial wall and become macrophages

- convert oxidized LDL into "foam cells" which form fatty streaks then plaque

Cholesterol

- lipid made in livers

- acts as a stabilizer for cell-membranes and used for cell to cell communication

- precursor to steriod hormones and vitamin D

Statins

- drugs used to lower cholesterol in the bloodstream

- target rate limiting enzyme in mevalonate pathway ( HMG-CoA reductase)

Monacolin K

chemical found in red yeast rice that was found to inhibit HMG-CoA reductase

Mevinolin

chemical found in fungi that is a lovastatin

Pharmacovigilance

activities related to the collection, detection, assessment and prevent of adverse reactions due to pharmaceuticals

Nutrivigilance

activities related to collection, detection, assessment, and prevention of adverse reactions due to dietary supplements, functional foods, and other nutraceuticals

FDA regulations

- does not have to approve dietary supplements for safety and effectiveness

- does not evaluate claims made about dietary supplements

- does inspect facilities for compliance with labeling and quality

Functions of skin

- Protection

- Cutaneous sensation

- Regulation of body temperature

- Absorption and excretion

- Vitamin D synthesis

Intrinsic damage

- Caused by the natural aging process. - Internal, physiological factors

Extrinsic damage

- caused by external factors

- UV solar radiation, visible and infrared radiation, tobacco, air pollution, diet, some cosmetic products

Free radical

- molecule with an unpaired valence electron which makes it highly reactive and usually short lived

- can start damaging chain reactions when reacting with biomolecules

Antioxidant

- molecule that is stable with a paired or unpaired electron and can thus donate an electron to a free radical molecule without becoming a free radical

- quenches singlet oxygen

ROS

- reactive oxygen species

- singlet oxygen, free radical, hydroxyl radical, hydrogen peroxide

- can cause oxidative damage by denaturing DNA and proteins and peroxidation of lipids

Age associated dermal microenvironment

- generated by ROS-mediated signaling events

- undermines skins structural and mechanical integrity

- increases production of MMPs (damages dermis

- reduces collagen production

- created proinflammatory microenvironment

Occlusive agents

block water loss via hydrophobic barrier

Humectants

draw water from the dermis to epidermis and form ambient humidity

Emollients

block water loss and replace missing natural lipids between dead skin cells

Protein rejuvenators

meant to replace missing things in dry skin