Paul J. Thornalley€¦ · Opportunity: Potential to gain health benefits associated with...

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New developments in the application of fruit bioactives for the treatment of NCDs Clinical Sciences Research Laboratories, Warwick Medical School, University Hospital, Coventry CV2 2DX, U.K. E: [email protected] Paul J. Thornalley Warwick Medical School - CSRL Seminar session Food Matters Live NCDs, dietary patterns and cardiovascular disease Thursday 23 rd November 2017, London ExCel

Transcript of Paul J. Thornalley€¦ · Opportunity: Potential to gain health benefits associated with...

Page 1: Paul J. Thornalley€¦ · Opportunity: Potential to gain health benefits associated with consumption of red grape juice – or better – without consumption of associated high sugar

New developments in the application of

fruit bioactives for the treatment of NCDs

Clinical Sciences Research Laboratories, Warwick Medical School,

University Hospital, Coventry CV2 2DX, U.K.

E: [email protected]

Paul J. Thornalley

Warwick Medical School - CSRL

Seminar session Food Matters Live

NCDs, dietary patterns and cardiovascular disease Thursday 23rd November 2017, London ExCel

Page 2: Paul J. Thornalley€¦ · Opportunity: Potential to gain health benefits associated with consumption of red grape juice – or better – without consumption of associated high sugar

Potential health benefits of fruit bioactives

in treatment of NCDs

UK Life expectancy

At birth:

Men 79 years

Women 83 years

Healthy Life expectancy

At birth:

Men 69 years

Women 71 years

At 65 years old:

Men 18 years

Women 21 years

At 65 years old:

Men 14 years

Women 16 years

GBD 2016 DALYs and HALE Collaborators Lancet 390, 1260–344, 2017

NCDs - include cancer, diabetes, chronic obstructive pulmonary

disease, cardiovascular disease, and mental health conditions

'Britain could soon be the sick man and

woman of Europe‘, Sir Michael Marmot;

demands answers from Jeremy Hunt as the

UK's life expectancy slows (10th Sept 2017)

Page 3: Paul J. Thornalley€¦ · Opportunity: Potential to gain health benefits associated with consumption of red grape juice – or better – without consumption of associated high sugar

Potential health benefits of fruit bioactives

in treatment of NCDs

We could achieve the same health benefits as a diet rich in

fruits …. or much better!

Cancer

Prevention of cancers of the gastro-intestinal tract, kidney and

bladder (IARC, WHO, 2003)

Heart disease

22% risk reduction (Crowe et al, Eur Heart J 32, 1235, 2011)

cf. statin, 40 mg/per day; risk reduction of 70%

Type 2 diabetes

24% risk reduction (3 servings Carter et al. BMJ 2010; 341, c4229)

cf. weight loss & increased physical activity, 58%

Safety If dietary bioactive supplements are given at doses no greater than

upper limits of dietary exposures, there is a precedent to expect

high clinical tolerability and safety

Page 4: Paul J. Thornalley€¦ · Opportunity: Potential to gain health benefits associated with consumption of red grape juice – or better – without consumption of associated high sugar

Crop sources of health beneficial compounds in

fruits and vegetables Citrus fruits, berries and olives

Red grapes

Polyphenols and flavonols

Nomilin

(from bitter orange)

Oleanolic acid

(from olive oil and garlic)

Triterpenoids

OHO

OH

OCH3

O

OH

Hesperetin

(from oranges)

Oranges Blueberries Strawberries Olives

trans-Resveratrol

(from grapes)

HO

OH

OH

Fisetin

(from strawberries)

OHO

OH

O

OH

OH

Cyanidin

(from blueberries)

Anthocyanins

OHO

OH

OH

OH

Page 5: Paul J. Thornalley€¦ · Opportunity: Potential to gain health benefits associated with consumption of red grape juice – or better – without consumption of associated high sugar

Opportunity: Potential to gain health benefits associated with

consumption of red grape juice – or better – without consumption of

associated high sugar content

Problem: Poor bioavailability at pharmaceutical doses

Safety

Minor clinical adverse effects observed at ≥1 g per day (diarrhoea or other gastrointestinal symptoms)

Serious adverse effect observed at 5 g per day (nausea, diarrhoea, fatigue, and renal toxicity – may have contributed to

one patient death in a clinical trial in 2010)

Long-term use – EFSA approved 150 mg per day as safe for long-

term use (EFSA Journal 14, 4368, 2016)

Health benefits of trans-resveratrol

HO

OH

OH

trans-Resveratrol (tRES)

Page 6: Paul J. Thornalley€¦ · Opportunity: Potential to gain health benefits associated with consumption of red grape juice – or better – without consumption of associated high sugar

Cancer prevention and treatment Few clinical studies performed. One patient died in a trial where tRES

(5g/day) dosing may have contributed to the death. Further studies unlikely

Cardiovascular disease Combined analysis or “meta-analysis” of clinical studies of 16 – 1000 mg

tRES per day claimed benefit against hypertension (decreased diastolic

blood pressure) at >150 mg/day by 11 mmHg

Problems: Effect driven by one, open label study. Evidence of

benefit is currently unreliable

Health benefits of trans-resveratrol

HO

OH

OH

trans-Resveratrol (tRES)

Page 7: Paul J. Thornalley€¦ · Opportunity: Potential to gain health benefits associated with consumption of red grape juice – or better – without consumption of associated high sugar

Obesity and prediabetes Combined analysis of clinical trials suggests there is no effect of tRES (10

mg – 2 g) on blood glucose, insulin resistance or body weight

Type 2 diabetes Combined analysis of clinical trials claimed benefit of 10 mg – 1 g

tRES/day on blood glucose, A1C and insulin resistance – Lui et al. Am J

Clin Nutr 99, 1510–1519, 2014

Problems: Effect driven by open label study & 2 poorly

randomised studies. Recent well-conducted trial found no

effect (Bo et al. Pharmacol Res 111, 896–905, 2016)

Evidence of benefit is currently unreliable

Health benefits of trans-resveratrol

HO

OH

OH

trans-Resveratrol (tRES)

Page 8: Paul J. Thornalley€¦ · Opportunity: Potential to gain health benefits associated with consumption of red grape juice – or better – without consumption of associated high sugar

Safety Highly tolerated. Normal consumption in orange juice:

30 – 40 mg HESP+ HESPD (mostly as HESPD).

Maximum dietary exposure up to ca. 1g per day HESP+ HESPD

Health benefits of Hesperetin/Hesperidin

OHO

OH

OCH3

O

OH

Hesperetin (HESP)

Hesperidin

(HESPD)

Opportunity: Potential to gain health benefits associated with

consumption of orange juice – or better – without consumption of

associated high sugar content

Problems: Poor bioavailability of HESPD

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Clinical studies

Small studies randomised, masked and open label studies

performed with 120 mg HESP or 296 - 500 mg HESPD

Benefits claimed: improved arterial function (dilatation)

Health benefits of Hesperetin/Hesperidin

OHO

OH

OCH3

O

OH

Hesperetin (HESP)

Hesperidin

(HESPD)

Health benefits of Anthocyanins

Blueberries Cyanidin

(from blueberries)

OHO

OH

OH

OH

Few studies performed with pure bioactives. Health benefits in

obesity/prediabetes may be available Stull et al., J Nutr 140, 1764–1768, 2010

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Benefits of bioactive combinations

may be the way forward Therapeutic benefits expected from trans-resveratrol (tRES) have not

been achieved because of poor absorption in the small intestines

This is overcome by combination with hesperetin (HESP). At doses of

>30 mg, Hesperetin is an effective inhibitor of intestinal glucuronidation,

facilitating uptake of unconjugated HESP and concurrently tRES

Intestinal wall (epithelium) Blood (basolateral side) Gut lumen

Efficient glucuronidation blocks

absorption of tRES

Little tRES

absorbed

tRES-HESP

combination: OH

OHO

OH

OCH3

OHESP

tRES

HO

OH

OH

HESP inhibits glucuronidation.

Remaining HESP and tRES is

absorbed

HESP

absorbed

tRES alone: tRES

absorbed

(Rabbani & Thornalley, Antioxidants & Redox Signalling, in press)

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Evaluation of tRES-HESP on metabolic and

vascular health in overweight/obese volunteers

Evaluation of tRES-HESP combination

Phase 1/Phase2A (obesity) clinical study

CLINICAL ENDPOINTS

■ Metabolic health - Oral glucose tolerance test (oGTT) –

derived insulin resistance measures (OGIS)

■ Vascular health – Arterial dilatation

■ Completed in 2015 – NCT02095873 (Clinicaltrial.gov)

STUDY DESIGN ■ Randomised, placebo-controlled, double blind crossover study,

8 wks treatment, 6 wks washout (n = 32)

■ Dose: 90 mg tRES-120 mg HESP, once daily

(Xue et al., Diabetes 65, 2282 – 2294, 2016)

Note: Doses cannot be obtained from grape & orange

juice - particularly without gross excess of sugar

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Variable Value

Age (years) 45 ± 13

Gender (M/F) 8/21

BMI (kg/m2) 30.0 ± 3.8

Overweight/Obese 18/11

Fasting plasma glucose (mM) 3.93 ± 0.57

A1C (%) 5.5 ± 0.7

Prediabetes (N/Y) 20/9

eGFR (ml/min) 97 ± 17

Systolic BP (mmHg) 133 ± 12

Diastolic BP (mmHg) 83 ± 10

Hypertension (N/Y) (18/11)

Subjects characteristics at study entry

Data are mean ± SD, median (lower – upper quartile)

or number of each classification; n = 29

Data are mean ± SEM *, P<0.05 (Xue et al., Diabetes 65, 2282 – 2294, 2016)

Evaluation of tRES-HESP combination

Phase 1/Phase2A (obesity) clinical study

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Effect on exposure to tRES and HESP

(assessed by urinary metabolites)

Data are mean ± SEM *, P<0.05

(Xue et al., Diabetes 65, 2282 – 2294, 2016)

Urinary metabolites of tRES Urinary metabolites of HESP

During tRES-HESP treatment, urinary metabolites of tRES and HESP

increased > 2000-fold and > 100-fold, respectively.

> 2000-fold

increase in tRES

> 100-fold

increased in HESP

Evaluation of tRES-HESP combination

Phase 1/Phase2A (obesity) clinical study

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Blood glucose control and insulin resistance outcome data:

Fasting

glucose

(FPG):

Meal-time

glucose

(PPG)

In highly overweight and obese

(BMI >27.5 kg/m2)

Glo1 inducer is safe, exhibits target clinical pharmacology and out-

performs current treatments in overweight/obese subjects

OGIS: (insulin resistance marker)

Data are mean ± SEM; *, P<0.05; ** P<0.01; paired t-test

(Xue et al., Diabetes 65, 2282 – 2294, 2016)

There was no effect of placebo

(+58 in obese subgroup)

Evaluation of tRES-HESP combination

Phase 1/Phase2A (obesity) clinical study

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What does +58 mlmin-1m-2 in OGIS

units mean? OGIS: Obesity: 6 months post-gastric band surgery

and extreme weight loss; + 62 mlmin-1m-2

Type 2 diabetes medication: 1.7 g metformin, + 54 mlmin-1m-2

With tRES-HESP, increased insulin sensitivity is driven

mainly by improved fasting and mealtime glucose control

(Xue et al., Diabetes 65, 2282 – 2294, 2016)

Evaluation of tRES-HESP combination

Phase 1/Phase2A (obesity) clinical study

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Profound anti-inflammatory effect

Study group Gene expression (Nanostring mRNA copy number profiling)

All IL8 (- 39%) and COX2 (- 30%)

Highly overweight &

obese (BMI ≥ 27.5 kg/m2)

IL8 (- 31%), COX2 (- 48%), CCL2/MCP1 (- 49%)

and RAGE (- 37%)

Major changes in gene expression in white blood cell with tRES-HESP

Note: peripheral blood mononuclear cells analysed

(Xue et al., Diabetes 65, 2282 – 2294, 2016)

IL8 (interleukin-8) is a mediator of vascular inflammatory

COX2 (cyclo-oxygenase-2) is a mediator of intestinal inflammation – a

target for cancer prevention

MCP1 and RAGE are mediators of vascular disease

■ tRES-HESP could find use in treatment of obesity, diabetes

and cancer prevention

Evaluation of tRES-HESP combination

Phase 1/Phase2A (obesity) clinical study

Page 17: Paul J. Thornalley€¦ · Opportunity: Potential to gain health benefits associated with consumption of red grape juice – or better – without consumption of associated high sugar

Evaluation of effect of tRES-HESP on metabolic and vascular

health in overweight/obese volunteers

Healthy Ageing Through Functional Food

(HATFF or Hats-off) Clinical Study

Development of novel functional foods at the University of Warwick

… first functional food supplement targeted to a specific gene

Glyoxalase 1 or Glo1 inducer functional food/pharmaceutical

Page 18: Paul J. Thornalley€¦ · Opportunity: Potential to gain health benefits associated with consumption of red grape juice – or better – without consumption of associated high sugar

Decreased glyoxalase 1 is associated with

■ Obesity

■ Diabetes

■ Increased risk of heart disease

■ Increased risk of some cancers

■ Decreased healthy lifespan

Why increase glyoxalase 1?

Increased glyoxalase 1 is associated with

■ Resistance to obesity

■ Prevention of type 2 diabetes

■ Prevention of complications of diabetes (kidney

disease, eye disease, peripheral nerve disease)

■ Decreased risk of heart disease

■ Prevention of some cancers

■ Increased healthy lifespan

Page 19: Paul J. Thornalley€¦ · Opportunity: Potential to gain health benefits associated with consumption of red grape juice – or better – without consumption of associated high sugar

New developments in the application of fruit bioactives for the

treatment of NCDs

SUMMARY

■ Dietary bioactive food supplements and pharmaceuticals offer

a safe and potentially effective opportunity to treat and

prevent of major NCDs

■ Initial promise of Resveratrol has been unfulfilled due to poor

clinical bioavailability

■ Combination of bioactives appears a way forward to improve

absorption and efficacy

■ trans-Resveratrol-Hesperetin (tRES-HESP) combination

produced unprecedented improvement in metabolic health in

overweight and obese subjects and may find use in treatment

of obesity and diabetes

Page 20: Paul J. Thornalley€¦ · Opportunity: Potential to gain health benefits associated with consumption of red grape juice – or better – without consumption of associated high sugar

Protein Damage and Systems Biology Research Group Team leaders:

Paul J. Thornalley Naila Rabbani

Dr Mingzhan Xue

Dr Jinit Masania

Dr Attia Anwar

Research team

Post-doctoral researchers

PhD students

Alaa Shafie

Amal Ashour

Daniah Alamoudi

Funding:

Grants: BBSRC, Wellcome Trust, Diabetes

UK, EU FP7 “BIOCLAIMS”, UK Innovate

UK/Unilever (UK)

Internal (Warwick) – colleagues in Medical School,

Systems Biology, Life Sciences, Chemistry and

Engineering;

UHCW – Dr Martin Weickert

Europe: EU FP7 BIOCLAIMS, EUTox – European renal

failure group, Peter Nawroth, Heidelberg, Germany.

USA: Michael Brownlee (New York), Andrezj Krolewski

(Boston)

Japan: Masi Yamamoto (Tohoku Univ, Sendai)

Australia – George Jerums and colleagues (Melbourne)

Key collaborators

Dr Sheheryar Qureshi

Louise Goodbody

Molly Waldron

Dr Martin Weickert

Clinical team

David Rand (Systems Biology)

Martin O

Weickert (Endocrinology,

UHCW)

“I keep the subject constantly before me…..”

Isaac Newton (on how he made discoveries)

Key collaborators: