This presentation will focus on data obtained from that authors' studies that test the efficacy of dried plum as a countermeasure against radiation-induced bone loss

Alwood, Joshua S.

Globus, Ruth K.

Schreurs, Ann-Sofie

Tahimic, Candice G. T.

NASA Technical Reports Server

Dried Plum as a candidate 
radiomitigant
Ann-Sofie Schreurs, Candice G. T. Tahimic, Joshua S. 
Alwood, Ruth K. Globus
NASA Ames Research Center, California, USA
1
https://ntrs.nasa.gov/search.jsp?R=20180004700 2019-08-31T15:30:44+00:00Z
Problem: Spaceflight conditions lead to bone loss
Microgravity Space Radiation
Healthy bone Osteoporotic bone 2
Space Radiation
Durante and Cucinotta 2011 
Norbury et al. 2016
Space radiation sources are: 
- Galactic Cosmic Rays (GCR)
- Solar Particle Events (SPE)
- protons and electrons trapped in the Earth's magnetic field
3
Space radiation is composed of a range of ions
- High-Z High Energy Ions (HZE)/ high Linear Energy Transfer (LET)
- low LET e.g. Protons 1H
Cucinotta, Durante,2006
Norbury et al. 2016
high LETlow LET
low LET
high LET (HZE)
Space Radiation
4
Radiation induces cancellous bone loss
HZE (56Fe) Iron; (50-100 cGy)
137Cs (Gamma)1H (Protons); (100-200 cGy)
 Bone Volume/Total Volume 
 Trabecular number
Schreurs et al, 2016
Alwood, Tran, Schreurs et al. 2017
5
Problem: Spaceflight conditions lead to bone loss
Microgravity Space Radiation
Healthy bone Osteoporotic bone 6
• Resistive exercises that mimic mechanical loading
(i.e.ARED)
• Bisphosphonate prevents BMD decrements (bone
mineral density), but has adverse effects. Also only acts
on the bone-resorptive osteoclasts.
7
Current methods for bone loss prevention
Spaceflight induced bone loss: possible 
mechanisms of action
 bone resorption via osteoclasts
 bone formation via osteoblasts
 oxidative stress and damage
 bone loss
8
9Tx: CD CD DP DP
IR: - + - +
Dried plum diet protects from bone loss caused by 
ionizing radiation
• Based on hypothesis, selected multiple antioxidants and/or anti-
inflammatory diets and drugs
• Diet composed of Dried Plums (DP) was the only effective one
• Prevents radiation-induced increase in markers of osteoclasts (Rankl,
Mcp1), inflammation (Tnf-a) and oxidative stress (Nrf2)
• Prevents bone loss due to radiation: low LET such as gamma (2Gy,
137Cs), and mix of protons and Iron (1Gy, 1H 56Fe)
Schreurs et al, 2016
Possible mechanisms of action
 bone resorption via osteoclasts
 bone formation via osteoblasts
 oxidative stress and damage
 bone loss (due to IR)
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DP acts on
LoadingDiet Radiation
Control Diet (CD)
Dried Plum diet (DP)
Normally loaded (NL)
Hindlimb unloaded (HU)
Sham
Irradiation (IR)
Sham
Irradiation (IR)
Normally loaded (NL)
Hindlimb unloaded (HU)
Sham
Irradiation (IR)
Sham
Irradiation (IR)
Experiment design
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Experiment design
Sham HU + IR
C
on
tr
ol
 D
ie
t
D
rie
d 
Pl
um
 D
ie
t
microCT images of the tibia after exposure to 
simulated weightlessness and ionizing radiation
Cortical 
bone
Cancellous 
bone
Dried Plum diet prevents cancellous bone loss in 
long bone (tibia)
Percent Bone 
Volume
Trabecular 
Thickness
Dried Plum diet prevents cancellous and cortical 
bone loss in axial bone (vertebrae)
Percent Bone 
Volume
Cortical 
Thickness
Dried Plum diet prevents bone strength decrease 
in axial bone (vertebrae)
*Ex-vivo osteoblastogenesis capacity when provided control versus 
dried plum diet and exposed to simulated weightlessness.
Dried Plum diet protects osteoblast progenitors
Does DP protect from high dose of HZE particles? Does 
it protect the osteoprogenitors?
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DP prevents from HZE induced cancellous bone loss 
(1Gy 56Fe)
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HZE
day 30
Tx: CD CD DP DP
IR: - + - +
Dried Plum protects marrow-derived osteoblast 
progenitors in mice exposed to HZE
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HZE
day 30
A broader, radiation countermeasure for multiple 
tissues?
Dietary DP prevents radiation-induced elevation in systemic marker of oxidative stress 
(serum TBARS)
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Gamma
DP: Possible mechanisms of actions
 bone resorption via osteoclasts
 bone formation via osteoblasts
 oxidative stress and damage
 bone loss (due to HU and IR)
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DP acts on
Dried Plum as potential spaceflight countermeasure
★ DP diet prevents bone decrements due to simulated 
spaceflight:
- Cancellous and cortical bone loss prevented 
- Bone quality and strength
★ DP diet fully prevents radiation-induced bone loss 
from low-LET and high-LET radiation:
- Relevance for both spaceflight and possibly 
radiotherapy patients
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★ DP protects marrow-derived osteoprogenitors:
- possible relevance to mesenchymal stem cells
★Mechanisms of DP :
- mitigating early increase in pro-osteoclast 
cytokines
- protecting the bone-forming osteoblasts 
- reduces oxidative stress and inflammation
- A multi-tissue solution?
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Dried Plum as potential spaceflight countermeasure
Questions that we may be able to address using RNAseq
data
1. What gene networks are responsive to DP?
2. What do these gene networks tell us about the possible 
mode of action DP?
3. What gene networks are responsive to ionizing radiation 
exposure? (Regardless of any observed microstructural 
changes)
4. Does DP prefeeding “prime” bone to defend against IR 
exposure?
What are the DP-specific responses to radiation?
106
CD IR vs 
CD Sham
DP IR vs 
DP Sham
45 175
Radiation effect:  
independent of diet
Compare
Downregulated genes
CD IR vs CD Sham: 151 DP IR vs DP Sham: 281
Unraveling DP diet-induced responses to ionizing 
radiation
Over representation 
analysis using 
WEBGESTALT
Cut-off: 1.4 fold change; 
Hence, Fold log 2 = 0.48
p ≤ 0.05 Benjamini corrected
Description # of genes FDR
Hematopoietic cell lineage - Mus musculus (mouse) 10 1.11E-05
Asthma - Mus musculus (mouse) 6 2.21E-05
Platelet activation - Mus musculus (mouse) 10 4.35E-05
Staphylococcus aureus infection - Mus musculus (mouse) 7 6.40E-05
Antigen processing and presentation - Mus musculus (mouse) 8 0.00021852
Intestinal immune network for IgA production - Mus musculus (mouse) 6 0.00021852
Toxoplasmosis - Mus musculus (mouse) 8 0.00076871
Rheumatoid arthritis - Mus musculus (mouse) 7 0.00076871
Leishmaniasis - Mus musculus (mouse) 6 0.00179921
Th17 cell differentiation - Mus musculus (mouse) 7 0.00218071
Tuberculosis - Mus musculus (mouse) 9 0.00218071
Phagosome - Mus musculus (mouse) 9 0.00244633
Systemic lupus erythematosus - Mus musculus (mouse) 8 0.00244633
Th1 and Th2 cell differentiation - Mus musculus (mouse) 6 0.00541676
Cell adhesion molecules (CAMs) - Mus musculus (mouse) 8 0.0061156
Inflammatory bowel disease (IBD) - Mus musculus (mouse) 5 0.0061156
Allograft rejection - Mus musculus (mouse) 5 0.0084218
Graft-versus-host disease - Mus musculus (mouse) 5 0.00854804
Type I diabetes mellitus - Mus musculus (mouse) 5 0.01140061
Autoimmune thyroid disease - Mus musculus (mouse) 5 0.01876814
Influenza A - Mus musculus (mouse) 7 0.02477853
Complement and coagulation cascades - Mus musculus (mouse) 5 0.02624234
Viral myocarditis - Mus musculus (mouse) 5 0.02640207
DP-specific responses to IR: downregulated gene networks
KEGG Pathways
DP-specific responses to IR: downregulated gene networks
Reactome Pathways
Description # of genes FDR
Hemostasis 24 3.02E-08
Platelet activation, signaling and aggregation 14 9.87E-05
Platelet degranulation 9 0.00140932
Response to elevated platelet cytosolic Ca2+ 9 0.00143111
Immune System 32 0.00372541
Common Pathway of Fibrin Clot Formation 4 0.01420829
Platelet homeostasis 5 0.02983486
Neutrophil degranulation 14 0.03487056
Innate Immune System 23 0.03487056
Rheumatoid arthritis-related genes are downregulated in bones of 
DP-fed animals exposed to IR
Genes associated with phagosome formation and lysosomal fusion 
are downregulated in bones of DP-fed animals exposed to IR
Cell adhesion genes are downregulated in bones of DP-fed animals 
exposed to IR
68
CD IR vs 
CD Sham
DP IR vs 
DP Sham
74 43
Radiation effect: 
independent of diet
Compare
Upregulated genes
CD IR vs CD Sham: 142 DP IR vs DP Sham: 111
Unraveling DP diet-induced responses to ionizing 
radiation
Over representation 
analysis using 
WEBGESTALT
Cut-off: 1.4 fold change; 
Hence, Fold log 2 = 0.48
p ≤ 0.05 Benjamini corrected
Upregulated genes in response to IR in CD group (all 
genes)
DNA 
damage 
response
Inflammatory 
cytokines
Upregulated genes in response to IR in DP group (all 
genes)
Downregulated genes in response to IR in CD group (all 
genes)
Downregulated genes in response to IR in DP group (all 
genes)
Myeloperoxid
ase
Inflammatory 
cytokine
Adhesion 
molecule
Inflammatory 
cytokine
Drugs that act on genes downregulated by IR in DP-treated 
mice (Top 20)
Cox-2 inhibitor NSAID
Drugs that act on genes upregulated by IR in DP-treated 
mice (Top 20) Dietary supplement and drug given to patients 
with AD and senile dementia; increases lifespan 
of mice
Drugs that act on genes upregulated by IR in CD-treated 
mice (Top 20)
(Chemotherapy drug)
Summary
Bones from animals pre-fed with DP displayed 
downregulation of pathways related to:
• Adhesion
• Inflammation (RA) 
• phagosome maturation/lysosomal fusion pathways
DNA damage response genes were upregulated in CD-fed 
group that received IR; these genes not observed in DP-fed 
animals exposed to IR
DP appears to protect from IR-induced DNA damage, 
inflammation and pro-adhesion events in bone
Sonette Steczina
Moniece Lowe
Samantha Torres 
Ons M’Saad 
Bernard Halloran (UCSF)
Gabriella Loots (LLNL)
Aimy Sebastian (LLNL)
Nicholas Hum (LLNL)
Josh Alwood’s lab
Eduarduo Almeida and Liz Blaber’s Labs
BNL and NSRL teams
SLSTP program
Funding
HRP HHC Omnibus 15-15Omni2-0039 (PI: 
Schreurs)
NASA Postdoctoral Program – Space Biology
NSBRI Grant #MA02501 (PI: Globus)
42
“Ground control to major Tim…”
https://www.nature.com/articles/srep21343
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Dried Plum as a Candidate Radiomitigant

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