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.
Paul J. Thornalley
Warwick Medical School - CSRL
Seminar session Food Matters Live
NCDs, dietary patterns and cardiovascular disease Thursday 23rd November 2017, London ExCel
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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)
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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
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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
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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)
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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)
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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)
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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
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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
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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
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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
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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: