inflammation and disease

8/13/2019 Inflammation and Disease

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INFLAMMATION &

DISEASEJessica Nagelkirk, NDSeptember 27, 2013

Marquette General Hospital

Nutrition and Medicine Conference


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Disclosures


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Wait, youre an ND not an MD?

Naturopathic physicians are primary care providers who

have graduated from an accredited 4-year medical school

after obtaining a bachelor degree that includes pre-

medicine studies. Complete nearly identical training in the basic sciences,

physical, laboratory, and imaging diagnostics,

pharmacology, and minor surgery procedures as

conventional medical school. Pass a national board examination comparable to the

USMLE step 1, 2, and 3 board examination.

Complete a residency program in family medicine.


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In addition to conventional training

Naturopathic physicians are experts in the use of

Nutritional IV Therapy

Clinical Nutrition

Botanical Medicine

Lifestyle Counseling

Environmental Medicine

Physical Medicine

Hydrotherapy

Homeopathy


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Prasad S, et al. Age-associated chronic disease required age-old medicine: chronic ifnlammation. Prev Med. 2012 May; 54


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Inflammation and Disease

Inflammation occurs by both immune and non-immune

mediated mechanisms.

Both pathways lead to the production of reactive oxygenspecies (ROS), that alter cell metabolism, genes, and

epigenetics.

This sustained inflammatory/oxidative environment leadsto a vicious cycle eventually moving from physiologic

dysfunction to true physical pathology.


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Immune Mediated Mechanism


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Phospholipid/ Non-Immune Mechanisms

Linoleic Acid Arachidonic Acid Alpha-Linoleinic Acid

From plant based omega-6 fatty

acids like nuts, seeds, grains,

etc

From animal based omega-6

fatty acids

From fish and plant based

omega-3 fatty acids like flax

GLAEPAFound in borage, black currant,

evening primrose, human milk

Leukotrienes PGE2

COX I & II

5-lipoxygenase

DHA

PGE3

PGE1

Delta-5 Desaturase

Delta-6 Desaturase

Delta-6 Desaturase

Note: Some people are deficient in delta-6 desaturase, an

enzyme promoted by vitamin B3, B6, Mn, C, E and inhibited

by alcohol and stress.

DGLA


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Inflammation and Alterations

Gastroenterology 2012; 143:550-563 (DOI:10.1053/j.gastro.2012.07.009 )


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ROS-Linked Pathology

Diseases

Acute respiratory distress syndrome

Aging

Alzheimer

Atherosclerosis

Cardiovascular disease

Diabetes

Inflammation

Inflammatory joint disease

Neurological disease

Obesity Parkinson

Pulmonary fibrosis

Rheumatoid arthritis

Vascular disease

Cancer

Bladder

Brain

Breast

Cervical (secondary to HPV) Gastric

Liver

Lung

Melanoma

Multiple myeloma

Leukemia

Lymphoma Oral

Ovarian

Pancreatic

Prostate

sarcoma

Simone R, et al. Oxidative Stress, inflammation, & Cancer. Free Radical Biology and Medicine 2010


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Daily Aspirin

Aspirin is the acetylated form of salicylic acid.

It inhibits prostaglandin synthesis decreasing

inflammation but also causes GI bleeding.

Data concerning colorectal cancer has become verycompelling with regard to aspirins capacity to prevent

primary disease.

Recent data from multiple trials suggest that long-term

daily use of aspirin lowers risk for colorectal cancer.

Chronic inflammation has been linked to heart disease,

neurological disorders and cancer.


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Aspirin

Aspirin inhibits

cyclooxygenase

(COX)-1.

It also acetylatesCOX-2 turning

arachidonic acid

into the

intermediate 15-R-HETE which is

transformed into the

anti-inflammatory

ALT by neutrophils.

http://archives.focus.hms.harvard.edu/2004/Oct15_2004/anesthesia.html


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Aspirin and White Willow Bark (Salix alba)

Salix alba is considered to be the natural form and original

source of the modern aspirin.

Contains phenolic glycosides salicin and salicylic acid

It is the acetylation process of aspirin that allows it to act

on the COX-2 pathway decreasing inflammation.

White Willow Bark and other salicylate-containing herbs

are anti-inflammatory without danger to the stomach, but

do not utilize the same COX-2 pathway mechanism,

instead it down regulates COX expression.


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Anti-inflammatory Plant Constituents

Cyclooxygenase Inhibitors Flavonoids

Phenolic Phenylpropane derivatives

Naphthoquinones

Akyl amides Tannins

5-Lipoxygenase Inhibitors Phenolic structures

Arachidonic acid analogs

Long-chain unsaturated fatty acids

PAF Inhibitors Ginkgolides

Lignans and neolignans


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Plants Containing Steroid Precursors

Examples:

Glycyrrhiza gabrra

(Licorice)

Dioscorea villosa (Wild

Yam)

Most useful for auto-immune inflammation


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Essential Oil-Rich Plants

Examples: Matricaria recutita

(Chamomile)

Calendula officinalis

(Calendula) Hypericum perforatum (St.

Johns Wort)

Effective for digestivesystem inflammationwith taken PO. Effectivefor skin inflammationwhen used topically.


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Histamine Blocking

Examples:

Tanacetum parthenium

(Feverfew)

Scutellariabailcalensis(Chinese

Skullcap)

Ginkgo Biloba


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Inflammatory Enzyme Modulating

PhosphodiesteraseInhibitors Camellia sinensis (tansy)

Berberis (Oregon Grape)

Lipoxygenase Inhibitors Quercitin containing herbs

like Nettles

Cyclooxygenase

Inhibitors Salicylate containing herbs

like Betula (birch), Populus(Poplar), or Gaultheria(Wintergreen)


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Other Types

Many herbs seem to act in anti-inflammatory fashion but

have no known chemical anti-inflammatory component.

Coleus orskholii, Bupleurum, Tanacetum parthenium, Zingiber officinalis, Glycyrrhizaglabra, Scutellaria bicalensis, Panax ginseng, Crataegus oxyacantha, Zizphus, Asarum,

nidium, Phellodendron, Copis aponica, Allium cepa, Picrorrhiza kurroa, Tylophora

asthmatica, Capsella bursa, Ginkgo biloba, Camellia sinensis, Berberis, Schisandra,

Magnolia, Curcuma longa, Ananas comosus, Calendula officinalis, Matricaria spp,

Ficus elastica, Hypericum perforatum, Arnica montana, Vaccinium myrtillis, Silybum

marianum, Betula, Salix, Populis, Filipendula, Gaultheria, Spirea, Cimicifuga, Linumussitatissimum, Borago, Ribes, Onethera, Smilax, Yucca, Centella, Hemidesmmus,

Ganoderma, Coleus, Eleuthrococcus, Aloe vera, Lentinus, Chlorella, Cinnamomum,

Artemesia, Lavendula, Apium graveolens, Carica papaya, Eugenia, Commiphora

mukul, Angelica sinensis


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Turmeric (Curcuma longa)


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Turmeric

Effects

Anti-inflammatory

Antiplatelet aggregation

Antioxidant

Antimicrobial

Inhibits carcinogenesis

Carminative

Key Constituents

Essential Oil containing

sesquiterpene ketones,

zingiberene,phellandrene, sabinene,

cineole, and borneol

Yellow pigments known

as diarylheptanoids

including curcuminand

methoxylated curcumins


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Pharmacodynamics of Turmeric

Curcuminappears to undergo rapid biotransformation

during and after gastrointestinal absorption.

It has been found that 40-85% of an oral dose of curcumin

passes through the gastrointestinal tract unchanged.

Due to its low rate of absorption, it is often formulated

with bromelain and black pepper for increased absorption

as well as enhanced anti-inflammatory effects.

C l h N t l M di i C h i D t b


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Anti-inflammatory Activity of Turmeric

The anti-inflammatory activity of curcuminwas reported as farback as 1937. In an extension of this work, it was reported that oral doses of

curcuminpossess significant anti-inflammatory action in both acuteand chronic models.

MOA: Dual inhibitor of arachidonic acid metabolism viamodulation of COX-2, prostaglandins, leukotrienes, and othercytokine pathways in the pro-inflammatory signaling pathway.

Dual inhibitors of AA are attracting interest as anti-inflammatoryagents since they prevent potentially damaging effects ofincreased leukotriene production which can result from the useof only COX inhibitors such as aspirin.

Curcuma longa monograph. Natural Medicines Comprehensive Database


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Evidence Based Medicine

A search for Curcuma longa and inflammation on PubMed

yielded 162 results.

Are Curcuminoids Effective C-Reactive Protein-Lowering

Agents in Clinical Practice? Evidence from a Meta-Analysis.Phytother Res.2013 Aug 7. doi:10.1002/ptr.5045.

This meta-analysis found that ingestion of curcuminoids

significantly decreased CRP levels. The degree of effect was

dependent on bioavailability of curcuminoid compounds used

and the duration of use. The highest yield was amongst subject

ingestion a bio-availability improved curcuminoid for greater

than or equal to 4 weeks.
http://www.ncbi.nlm.nih.gov/pubmed/23922235http://www.ncbi.nlm.nih.gov/pubmed/23922235


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Immune-stimulatory and anti-inflammatory activities ofCurcuma longa extract and its polysaccharide fraction.Pharmacognosy Res.2013 Apr;5(2):71-9. doi: 10.4103/0974-8490.110527.Chandrasekaran CV, Sundarajan K, Edwin JR, Gururaja GM, MundkinajedduD,Agarwal A.

This study demonstrated that an aqueous solution ofcurcuma longa, devoid of curcuminoids, continued topossess anti-inflammatory qualities. This solutionappeared to inhibit IL-12 and PGE2 in vitro.

This study highlights the complexity of herbal therapeuticaction. Even when we identify a therapeutic action, thesynergistic action of the whole plant is often morecomplex.
http://www.ncbi.nlm.nih.gov/pubmed/23798880http://www.ncbi.nlm.nih.gov/pubmed?term=Chandrasekaran%20CV[Author]&cauthor=true&cauthor_uid=23798880http://www.ncbi.nlm.nih.gov/pubmed?term=Sundarajan%20K[Author]&cauthor=true&cauthor_uid=23798880http://www.ncbi.nlm.nih.gov/pubmed?term=Edwin%20JR[Author]&cauthor=true&cauthor_uid=23798880http://www.ncbi.nlm.nih.gov/pubmed?term=Gururaja%20GM[Author]&cauthor=true&cauthor_uid=23798880http://www.ncbi.nlm.nih.gov/pubmed?term=Mundkinajeddu%20D[Author]&cauthor=true&cauthor_uid=23798880http://www.ncbi.nlm.nih.gov/pubmed?term=Mundkinajeddu%20D[Author]&cauthor=true&cauthor_uid=23798880http://www.ncbi.nlm.nih.gov/pubmed?term=Agarwal%20A[Author]&cauthor=true&cauthor_uid=23798880http://www.ncbi.nlm.nih.gov/pubmed?term=Agarwal%20A[Author]&cauthor=true&cauthor_uid=23798880http://www.ncbi.nlm.nih.gov/pubmed?term=Mundkinajeddu%20D[Author]&cauthor=true&cauthor_uid=23798880http://www.ncbi.nlm.nih.gov/pubmed?term=Mundkinajeddu%20D[Author]&cauthor=true&cauthor_uid=23798880http://www.ncbi.nlm.nih.gov/pubmed?term=Gururaja%20GM[Author]&cauthor=true&cauthor_uid=23798880http://www.ncbi.nlm.nih.gov/pubmed?term=Edwin%20JR[Author]&cauthor=true&cauthor_uid=23798880http://www.ncbi.nlm.nih.gov/pubmed?term=Sundarajan%20K[Author]&cauthor=true&cauthor_uid=23798880http://www.ncbi.nlm.nih.gov/pubmed?term=Chandrasekaran%20CV[Author]&cauthor=true&cauthor_uid=23798880http://www.ncbi.nlm.nih.gov/pubmed/23798880


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Curcumin: an orally bioavailable blocker of TNF andother pro-inflammatory biomarkers. Br J Pharmacol.2013Aug;169(8):1672-92. doi: 10.1111/bph.12131.Aggarwal BB, Gupta SC,Sung B.

This meta-analysis examines curcuma longas effects onTNF and discusses its role as an adjunct or substitute topharmacologic TNF blockers.

This analysis references studies from as early as 1937

demonstrating efficacy of turmeric in treating inflammatorydiseases in patients.

There are studies documenting curcuminsefficacy intreating many inflammatory diseases includingrheumatoid arthritis, IBD, many cancers, diabetes, andheart disease.
http://www.ncbi.nlm.nih.gov/pubmed/23425071http://www.ncbi.nlm.nih.gov/pubmed?term=Aggarwal%20BB[Author]&cauthor=true&cauthor_uid=23425071http://www.ncbi.nlm.nih.gov/pubmed?term=Gupta%20SC[Author]&cauthor=true&cauthor_uid=23425071http://www.ncbi.nlm.nih.gov/pubmed?term=Sung%20B[Author]&cauthor=true&cauthor_uid=23425071http://www.ncbi.nlm.nih.gov/pubmed?term=Sung%20B[Author]&cauthor=true&cauthor_uid=23425071http://www.ncbi.nlm.nih.gov/pubmed?term=Gupta%20SC[Author]&cauthor=true&cauthor_uid=23425071http://www.ncbi.nlm.nih.gov/pubmed?term=Aggarwal%20BB[Author]&cauthor=true&cauthor_uid=23425071http://www.ncbi.nlm.nih.gov/pubmed/23425071


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Comparative evaluation of the pain-relieving properties of alecithinized formulation of curcumin (Meriva()), nimesulide, andacetaminophen.J Pain Res.2013;6:201-5. doi: 10.2147/JPR.S42184. Epub 2013 Mar 8.Di Pierro F, Rapacioli G, Di Maio EA,Appendino G, Franceschi F, Togni S.

This pilot study investigated the acute analgesic activity of the curcumin

derivative Meriva. Meriva was compared to nimesulide and acetaminophen and

demonstrated an effect comparable to acetaminophen but less thannimesulide. Meriva was more well tolerated than nimesulide andcomparable to nimesulide. Meriva was utilized at a larger dose than forchronic inflammation (2 g vs 500 mg) in order to achieve this acuteanalgesic effect.

The effect is thought to stem from COX 2 inhibition and desensitization ofreceptor potential A1 (a receptor that also mediates the analgesic effectsof acetaminophen). Additionally, the authors speculate that the long termattenuation of inflammation from the acute supplementation of Merivawould lead to better control of acute pain.

Mills S, Bone K. Principles & Practice of Phytotherapy
http://www.ncbi.nlm.nih.gov/pubmed/23526055http://www.ncbi.nlm.nih.gov/pubmed?term=Di%20Pierro%20F[Author]&cauthor=true&cauthor_uid=23526055http://www.ncbi.nlm.nih.gov/pubmed?term=Rapacioli%20G[Author]&cauthor=true&cauthor_uid=23526055http://www.ncbi.nlm.nih.gov/pubmed?term=Di%20Maio%20EA[Author]&cauthor=true&cauthor_uid=23526055http://www.ncbi.nlm.nih.gov/pubmed?term=Appendino%20G[Author]&cauthor=true&cauthor_uid=23526055http://www.ncbi.nlm.nih.gov/pubmed?term=Franceschi%20F[Author]&cauthor=true&cauthor_uid=23526055http://www.ncbi.nlm.nih.gov/pubmed?term=Togni%20S[Author]&cauthor=true&cauthor_uid=23526055http://www.ncbi.nlm.nih.gov/pubmed?term=Togni%20S[Author]&cauthor=true&cauthor_uid=23526055http://www.ncbi.nlm.nih.gov/pubmed?term=Franceschi%20F[Author]&cauthor=true&cauthor_uid=23526055http://www.ncbi.nlm.nih.gov/pubmed?term=Appendino%20G[Author]&cauthor=true&cauthor_uid=23526055http://www.ncbi.nlm.nih.gov/pubmed?term=Di%20Maio%20EA[Author]&cauthor=true&cauthor_uid=23526055http://www.ncbi.nlm.nih.gov/pubmed?term=Rapacioli%20G[Author]&cauthor=true&cauthor_uid=23526055http://www.ncbi.nlm.nih.gov/pubmed?term=Di%20Pierro%20F[Author]&cauthor=true&cauthor_uid=23526055http://www.ncbi.nlm.nih.gov/pubmed/23526055


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Turmeric in Clinical Practice

Preparations: Dried root may be used as a decoction; liquid extract, or capsules.

Dosage:

Powdered rhizome provided at a heaped teaspoon (about 4 grams)mixed with water to a slurry and drank 1-2 times daily. A teaspoon oflecithin can be added to improve absorption.

1:1 liquid extract using 45% ethanol or higher recommended at 5-14ml per day best taken in 4 equal doses throughout the day

Encapsulated common sig is 500 mg QID

Duration of use & safety: May be taken long term within the recommended dosages. No

adverse effects from ingestion of turmeric have been documented atthe recommended dosages.

Mills S, Bone K. Principles & Practice of Phytotherapy


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Omega-3 Fatty Acids


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Eicosanoids & Inflammation

Eicosanoids are signaling molecules made byoxygenation of 20-carbon PUFAs

Metabolism product of COX and LOX enzymes

Modulate:

Cell growth and differentiation Intensity and duration of inflammatory response

Immunity

Platelet Aggregation

Angiogenesis

Include: Prostaglandins (PG)

Thromboxanes (TX)

Leukotrienes (LT)


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EPA and DHA

>15,000 studies

published in past 40

years on health

benefits of EPA & DHA

EPA and DHA are

natural COX-2

inhibitors


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Conversion Pathway of Omega-3 FA

Alpha-Linolenic Acid (ALA)18:3n-3

Stearidonic Acid

18:4n-3

Eicosatetraenoic Acid20:4n-3

Eicosapentaenoic Acid (EPA)

20:5n-3

Docosapentaenoic Acid (DPA)

22:5n-3

Docosahexaenoic Acid (DHA)

22:6n-3

Anti-Inflammatory

Resolvins & Protectins

Flax, hemp, canola oilsand walnuts

Hemp, modified

vegetable oils, fish

Fish, Fish Oil

Fish, Fish Oil, Algae

6-desaturaseCofactors: B3, B6, Mg, Zn Vit C

Inhibited: alcohol, trans fats,

diabetes, hyperinsulinemia

Dong-Soon IM. Omega-3 fatty acids in anti-inflammation on GPCRs. Progress in Lipid Research. July 2012. 51(3):232-237


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Resolvins & Protectins

Anti-inflammatory actions that lead to the resolution ofthe inflammatory cycle

Experimental evidence indicates that resolvins and

protectins reduce cellular inflammation by stoppingexcessive neutrophil infiltration and clearing apoptoticPMN leukocytes from sites of inflammation

They are synthesized from either eicosapentaenoic acid(EPA) or docosahexaenoic acid (DHA)

Both series of resolvins (E and D) increase with use oflow dose aspirin or supplementation with EPA/DHA

g g y g p y ( )


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N-3 polyunsatruated fatty acids: relationship to

inflammation in healthy adults and adults exhibiting

features of metabolic syndrome.

Robinson LE, Mazurak VC. Lipids. 2014 Apr;48(4)319-32.

This review article supports the recommendation that a diet

rich in omega-3 fatty acids plays a role in the prevention

and reduction of inflammation.


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Omega-3 fatty acids and inflammatory processes.

Calder PC. Nutrients. 2010 Mar;2(3);355-74

This review article evaluated the mechanisms in which EPA

and DHA modulate inflammation in which they concluded a

variety of mechanisms were involved. Anti-inflammatory

actions of marine n-3 PUFAs were specifically identified to

be useful in inflammatory conditions including RA and

atherosclerosis, however the authors speculate n-3 PUFAswould be useful in nearly all inflammatory conditions due to

the known MOA.

Williams CM, Burdge G. Long-chain n-3 PUFA: Plant v. marine sources. Proc Nutr Soc. 2006 Feb; 65(1):42-50


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Is Conversion of ALA to LCPUFA

Efficient?

ALA

18:3n-3

EPA

20:5n-3

DPA

22:5n-3

DHA

22:6n-3

0.2-8% Conversion

0.13-6% Conversion

Trace- 0.5% Conversion

An intake of 2 grams

of ALA would yield

approximately 160mg EPA at a

conversion rate of

8% and

approximately 10 mg

DHA at a conversion

rate of 0.5%.


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Omega-3 as Inflammatory Modulator in

Clinical Practice Ratio

1:2 EPA:DHA

Dose

3 grams EPA+DHA po qd

Reference

Health Canada

Warning: Make sure to have your patients purchase

products that undergo third party testing for purity and

content.

Giugliano D, et al. The effects of diet on inflammation. Journal of Amer Col Card. 2006. 48(4)


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Anti-Inflammatory Diet

Low consumption of fruit and vegetables, together with physical inactivity, are

now among the top 10 causes of mortality in developed countries.


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What is an anti-inflammatory diet?

It depends who you ask.

Several different versions, that all have the same basic

guidelines:

Increase omega-3 fatty acids

Increase anti-oxidants

Decrease processed foods

Decrease alcohol and caffeine

Eliminate known allergens

Eliminate sugar

Some guidelines go further and eliminate:

Nightshade vegetables (potato, tomato, eggplant, bell peppers etc.)

Common allergens like soy, peanuts, gluten, dairy, & eggs

Sears B, Ricordi C. Anti-inflammatory nutrition as a pharmacological approach to treat obesity. J Obes. 2011


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MOA of Diet and Inflammation

Dietary intake of arachidonic acid up-regulates

prostaglandin synthesis.

Increased prostaglandin and inflammation leads to insulin

resistance and lipid oxidation.

This leads to increases in silent inflammation and

obesity.

Greater intake of antioxidant containing foods reduces

inflammatory cytokines and mitigates this process.


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Inflammation and Disease

Inflammation has been implicated in many chronic

diseases.

There are many ways to decrease inflammation through

diet and lifestyle.

Herbs and fish oil are a helpful adjunct to these

interventions.

By addressing inf lammation as a preventive measure,

we can work towards in creasing qual i ty of l i fe and

decreasing morbid i ty and mortali ty in ou r pat ients.


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Contact Information

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503-552-1874
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