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2 Featured Article 57
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4 Neuroprotective effect of a new photobiomodulation technique against 59
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6 Ab25–35 peptide–induced toxicity in mice: Novel hypothesis for 61
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8Q3 therapeutic approach of Alzheimer’s disease suggested 63
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11Q22 Guillaume Bliveta, Johann Meunierb, Francois J. Romanb,*, Jacques Touchonc,d,e 66
12 a
REGEnLIFE, Montpellier, France 67
13 b
Amylgen, Montferrier-sur-Lez, France 68
14
c
INSERM U1061, Montpellier, France 69
d
15 Montpellier University, Montpellier, France 70
e
16 JT Conseils, Montpellier, France 71
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19Q1 Abstract ---. 74
20 Ó 2018 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an 75
21 open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 76
22 4.0/). 77
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Keywords: ---
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1. Introduction such as inflammation downregulation, repair processes, and
28 83
tissue healing stimulation [5], for treatments in neurology 84
29 Alzheimer’s disease (AD), the main cause of dementia, is
30
and neuropsychiatry [6]. Neuroprotective efficacy of PBM 85
a major public health issue [1] in light of the burden it places
31 is now well established and adds a unique value to promising 86
on patients, families, and caregivers as well as its socioeco-
32 therapies because it has been proven safe and effective in 87
nomic impact. Despite the considerable research advances
33 humans [7]. PBM treatment ameliorates neuropathology 88
made and promising data obtained recently with aducanu- 89
34 and disease progression in a mouse transgenic model of
35
mab [2], no real effective treatment has been identified to 90
AD [8,9]. Recently, pilot clinical trials on patients with
36 date. Therefore, combination of innovative treatments, 91
dementia and AD indicate significant cognitive
37 engaging not only one target but several ones, is currently 92
improvement [10–12], suggesting that transcranial PBM is
38 mandatory to hope to treat this complex neurodegenerative a potential candidate for treatment of AD. In this article, 93
39 disorder. In this article, we describe a treatment based on a 94
we describe an innovative device, RGn500, combining
40 noninvasive electromagnetic technology, called photobio- 95
different technologies producing photonic and magnetic 96
41Q5 modulation (PBM). The use of LEDs or lasers in PBM has
42
field emissions. This neuro-magneto-photonic treatment 97
been shown to induce a photochemical reaction within the
43 combines PBM with a static magnetic field in addition. 98
cell [3], causing an increase in mitochondrial function and
44 Low static magnetic field has been studied in animal models, 99
ATP synthesis. Such parameters suggest a neuroprotective
45 and transcranial magnetic stimulation with a high magnetic 100
effect, especially relevant to AD pathogenesis where mito- 101
46 field has been investigated as a noninvasive therapeutic tool
47
chondrial proteostasis is particularly affected [4]. Several to treat neurological and psychiatric diseases [13]. The impli- 102
48 studies report astonishing properties of transcranial PBM, 103
cation of various altered processes in AD, such as mitochon-
49 drial dysfunction [14] or inflammatory processes [15], 104
50 support transcranial stimulation. Alternative hypotheses 105
51 106
point the importance of brain-gut axis in neurodegenerative
52 The authors have declared that no conflict of interest exists. 107
*Corresponding author. Tel.: 133-(0)675-935-266. diseases [16] and suggest the interest of an abdominal 108
53Q4
54 E-mail address: froman@orange.fr stimulation. 109
https://doi.org/10.1016/j.trci.2017.12.003
2352-8737/ Ó 2018 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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167 Fig. 1. Effect of RGn500 treatment on Ab25–35 (AB25–35)–induced deficits in the spontaneous alternation test. Different times of exposure, the frequency (once 228
168 a day [o.d.] or twice a day [b.i.d.]), and the mode of delivery with exposure of head alone (at 10 Hz), of abdomen alone (at 1000 Hz), or of both body parts (h/a) 229
169 were examined. Data are presented as mean 6 SEM. ***P , .001 versus Sc Ab (Sc.AB) group; ##P , .01, ###P , .001 versus Ab25–35 group. n 5 12–21 per Q21 230
170 group. Abbreviation: Ab25–35, amyloid b peptide 25–35. Q19 Q20 231
232 A B 293
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Fig. 2. Effect of RGn500 treatment on Ab25–35 (AB25–35)–induced deficits in the step-through latency (A and C) and the escape latency (B and D) in the pas-
282 343
sive avoidance task. Different times of exposure, the frequency (once a day [o.d.] or twice a day [b.i.d.]), and the mode of delivery with exposure of head alone (at
283 344
10 Hz), of abdomen alone (at 1000 Hz), or of both body parts (h/a) were examined. Data are presented as mean 6 SEM. ***P , .001 versus Sc Ab (Sc.AB)
284 group; ##P , .01, ###P , .001 versus Ab25–35 group. n 5 12–21 per group. Abbreviation: Ab25–35, amyloid b peptide 25–35. 345
285 346
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287 (1000 Hz) (117.4% 6 4.4), F (5, 29) 5 14.75, P , .001, Dun- 2.3. Inflammation 348
288 nett’s test after one-way ANOVA (Fig. 3A). 349
289 When the treatment was only localized on the head or Inflammatory processes were measured in the hippocam- Q9 350
290 abdomen, RGn500 application did not produce any signifi- pus 9 days after Ab25–35 peptide i.c.v. injection in mice, in 351
291 cant beneficial effect (Fig. 3B). terms of GFAP, TNFa, IL-1b, IL-6 level measurement by 352
292 353
354 A B 415
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377 Fig. 3. Effect of RGn500 treatment on Ab25–35 (AB25–35)–induced increase of lipid peroxidation. Different times of exposure, the frequency (once a day [o.d.] 438
378 or twice a day [b.i.d.]), and the mode of delivery with exposure of head alone (at 10 Hz), of abdomen alone (at 1000 Hz), or of both body parts (h/a) were 439
379 examined. Data are presented as mean 6 SEM. *P , .05, ***P , .001 versus Sc Ab (Sc.AB) group; ###P , .001 versus Ab25–35 group. n 5 6 per group. 440
380 Abbreviation: Ab25–35, amyloid b peptide 25–35. 441
381 442
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ELISA assay, and astrocyte and microglia activation evalu- (Fig. 4C and 4F). However, RGn500 very significantly Q10
383 444
ated by immunohistochemical analyses of brain slices in reduced the level of IL-1b and IL-6 when animals were
384 445
385 the CA1 region of the hippocampus. treated simultaneously during 10 minutes on the head 446
386 Ab25–35 peptide injection induced a significant increase of (10 Hz) and abdomen (10 Hz) (Fo IL-1b 55.7% 6 4.5, 447
387 GFAP levels (154.8% 6 11.3) (Fig. 4A). The RGn500 appli- F (2, 17) 5 31.22, P , .001, for IL-6 46.7% 6 6.0, 448
388 cation on both the head (10 Hz) and abdomen (1000 Hz) (h/a) F (2, 17) 5 27.97, P , .001, Dunnett’s test after one-way 449
389 triggered a reduction of the inflammation with a total reversal ANOVA). 450
390 for 10 minutes, whereas a 20-minute treatment was inactive The injection of Ab25–35 peptide oligomers produced the 451
391 [(145.8% 6 8.6), F (5, 40) 5 4.283, P , .01, Dunnett’s test appearance of typical activated astrocytes (Fig. 5B) charac- 452
392 after one-way ANOVA; Fig. 4A]. When the treatment was terized by a change in shape consisting particularly in an 453
393 localized only on the head or abdomen, RGn500 failed to pro- important ramification compared to resting astrocytes in 454
394 455
duce any beneficial effect (respectively, 177.4% 6 14.8, and the Sc Ab group (Fig. 5A). The significant increase in the
395 456
175.4% 6 7.6, F (4, 33) 5 6.692, P , .001, Dunnett’s test number of activated astrocytes was normalized after daily
396 457
397 after one-way ANOVA) (Fig. 4B). treatment with RGn500 applied during 10 minutes on both 458
398 Ab25–35 peptide induced a very significant increase of the head and abdomen (Fig. 5G). 459
399 TNFa levels (184.8% 6 17.3) (Fig. 4D). RGn500 applica- Iba-1 immunolabeling showed a significantly modified 460
400 tion reduced this increase after 5, 10, and 20 minutes of microglial activity. Strongly labeled fluorescent cells ex- 461
401 simultaneous application on the head (10 Hz) and abdomen hibited typical amoeboid morphology and few ramifications 462
402 (1000 Hz) (127.5% 6 12.9), F (5, 51) 5 6.761, P , .001, indicative of activated microglia as compared to surveilling 463
403 Dunnett’s test after one-way ANOVA, (Fig. 4D). type (Fig. 5E). 464
404 When the treatment was only localized on the head or the The daily treatment with RGn500 applied during 465
405 abdomen, RGn500 failed to yield any beneficial effect 10 minutes on both the head (10 Hz) and abdomen (10 Hz) 466
406 (respectively, 140.5% 6 13.9, and 143.9% 6 12.2, inhibited this microglial activation (Fig. 5F) in a highly sig- 467
407 468
F (4, 43) 5 6.073, P ,.001, Dunnett’s test after one-way AN- nificant manner (P , .001, Fig. 5H).
408 469
409 OVA) (Fig. 4E). Similar results were found after an applica- 470
410 tion of RGn500 on both the head (10 Hz) and abdomen 471
2.4. Mitochondrial markers of apoptosis
411 (10 Hz) during 10 minutes (results not shown). The following 472
412 experiments were conducted under these conditions. The level of pro-apoptotic Bax and the anti-apoptotic 473
413 IL-1b and IL6 hippocampal levels were not modified by Bcl2 markers were measured in the hippocampus 10 days af- 474
414 Ab25–35 peptide injection as compared to Sc Ab injection ter Ab25–35 peptide oligomer i.c.v. injection in mice, by 475
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512 Fig. 4. Effect of RGn500 treatment on Ab25–35 (AB25-35)–induced increase of inflammatory processes. Different times of exposure, the frequency (once a day 573
513 [o.d.] or twice a day [b.i.d.]), and the mode of delivery with exposure of head alone (at 10 Hz), of abdomen alone (at 10 Hz), or of both body parts (h/a) were 574
514 examined. Data are presented as mean 6 SEM. *P ,.05, **P ,.01, ***P ,.001 versus Sc Ab (Sc.AB) group; #P ,.05, ##P ,.01, ###P ,.001 versus Ab25–35 575
515 group. n 5 6 per group. Abbreviation: Ab25–35, amyloid b peptide 25–35. 576
516 577
517 578
518 ELISA assay. An increase of the ratio Bax/Bcl2 translates an (10 Hz) [(0.956 6 0.030), F (2, 17) 5 6.437, P , .01, 579
519 induction of apoptosis due to the heterodimerization of Bax Dunnett’s test after one-way ANOVA; Fig. 6C]. 580
520 and Bcl2. 581
521 Ab25–35 peptide oligomers injection produced an in- 582
522 2.5. Amyloid processing and hyperphosphorylation of tau 583
crease of Bax levels (121.6% 6 5.8) that was not signifi-
523 protein 584
cant. RGn500 reduced the increase of Bax when the
524 585
525 animals were treated 10 minutes on the head (10 Hz) and Ab25–35 peptide induced a very significant augmentation 586
526 on the abdomen (10 Hz) [(108.9% 6 6.3), of Ab1–42 (115.5% 6 4.6) measured in the hippocampus 587
527 F (2, 17) 5 3.110, P . .05, Dunnett’s test after one-way 10 days after Ab25–35 peptide i.c.v. injection (Fig. 6D). 588
528 ANOVA; Fig. 6A]. RGn500 inhibited this increase when the animals were 589
529 No effect on Bcl2 levels was seen after Ab25–35 peptide treated for 10 minutes on the head (10 Hz) and the abdomen 590
530 oligomers injection and RGn500 application (Fig. 6B). (10 Hz) (86.3% 6 2.6), F (2, 17) 5 13.92, P , .001, Dun- 591
531 The Bax/Bcl2 ratio was significantly increased nett’s test after one-way ANOVA, (Fig. 6D). 592
532 (1.199 6 0.060) (Fig. 6C). RGn500 significantly reduced The levels of pTau-Thr181 were very highly increased 593
533 the increase of the ratio when animals were treated daily (698.3% 6 21.4) (Fig. 6E). RGn500 reduced this rise when an- 594
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for 10 minutes on the head (10 Hz) and the abdomen imals were treated for 10 minutes both on the head (10 Hz) and
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626 Fig. 5. Effect of RGn500 treatment on Ab25–35–induced activation of astrocytes (A–C, and G) and microglia (D–F, and H). Exposure was once a day of both the
687
627 head and abdomen for 10 minutes at 10 Hz on both body parts. **P , .01 versus Sc.Ab (Sc.AB) group; ***P , .001 versus Sc AB group; ###P , .001 versus 688
628 Ab25–35 (AB25–35) group. Abbreviation: Ab25–35, amyloid b peptide 25–35. 689
629 690
630 on the abdomen (10 Hz) (104.1% 6 5.1), F (2, 17) 5 686.8, various pharmacological substances (Appendix 2). The 691
631 692
P , .001, Dunnett’s test after one-way ANOVA (Fig. 6E). fact that PBM treatment produces a clear normalization of
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all parameters that are strongly modified in the model, 694
634 3. Discussion including memory performances associated to oxidative 695
635 stress, neuroinflammation, or apoptosis markers and not 696
636Q11
Our results clearly indicate that RGn500 application pro- only specific markers related to the amyloid or tau processes, 697
637 duces a neuroprotective effect in the Ab25–35 mouse model suggests that this treatment is mobilizing a large number of 698
638 when the light beam, with described parameters, was applied mechanisms. Only a very specific and limited mechanism 699
639 both to the head and abdomen but not when only to the head would be expected from a classical pharmacological inter- 700
640 or abdomen. Although this rodent model is far away from re- vention. From that observation, and given the complexity 701
641 producing the complexity of the physiopathological character- of the aimed pathology, it can be expected that the applica- 702
642 istics of dementia in humans, its features may be of interest for tion of PBM may produce better outcomes than a precise and 703
643 better understanding some of the underlying mechanisms. The 704
limited pharmacological treatment.
644 toxicity induced by the Ab25–35 peptide in oligomeric form has 705
645 been repeatedly shown to result 7 days after in neuroinflamma- 706
646 707
tion and reactive gliosis [18,19], pro-apoptotic caspases activ- 3.2. Dual mechanism of action
647 708
648
ity enhancement [18], oxidative stress [20], endogenously 709
produced amyloid protein deposition [18], tau protein hyper- Our results suggest two different mechanisms by which
649 NIR can induce neuroprotection: a direct stimulation of Q12 710
650 phosphorylation [18], and increase of kinases [21,22], a 711
the damaged cells and an indirect stimulation of as yet un-
651 reduction in the number of neurons measured in hippocampal 712
identified circulating mediators that transduce a protective
652 pyramidal cell layers [17,23], loss of cholinergic neurons 713
653 [24], and memory deficits [17,18,23,25–27]. effect to the brain. 714
654 There is strong evidence that photons that have wave- Q13 715
655 lengths in red or NIR spectrum are absorbed in CNS struc- 716
3.1. Efficacy of PBM treatment
656 tures by specific cellular chromophores localized in the 717
657 The efficacy of PBM treatment can be compared to what mitochondria. The crucial chromophore identified in the 718
658 has been found in the same model by daily treatment with mitochondria is cytochrome c oxydase also known as 719
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pTau Thr181 contents (% of Sc.AB)
*
AB1-42 contents (% of Sc.AB)
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757 Fig. 6. Effect of RGn500 on Ab25–35 (AB25–35)–induced increase of Bax and Bcl2 (A–C), Ab1-42 (AB1–42) (D) and pTau-Thr181. Exposure was once a day of 818
758 both the head and abdomen for 10 minutes at 10 Hz on both body parts. Data are mean 6 SEM. *P ,.05, ***P ,.001 versus Sc Ab (Sc.AB) group; ###P ,.001 819
759 versus Ab25–35 (AB25–35) group. n 5 6 per group. Abbreviation: Ab25–35, amyloid b peptide 25–35. Q2
820
760 821
761 complex IV. Photonic exposure causes an increase in elec- Indirect stimulation was first evidenced in patients with 822
Q14
762 823
tron transport and mitochondrial products, such as ATP, metastatic cancer: it was reported that localized radiation
763 824
NADH, NO, proteins, and RNA [28], leading to the self- therapy delivered to the patients can occasionally result
764 825
765 repair of the damaged cells, accelerating wound healing in the regression of tumors distant from the irradiation 826
766 and tissue regeneration, increasing circulation, and reducing site. Termed “abscopal effect”, this phenomenon is rare 827
767 inflammation and pain [7]. but widely reported and is believed to be mediated by a 828
768 Several studies have shown a real interest for transcranial systemic cytokine and/or immune response [35]. Bone 829
769 PBM treatment in neurology and neuropsychiatry with prom- marrow–derived stem cells, possibly mesenchymal stem 830
770 ising results on animals and humans in stroke [29], traumatic cells, have been identified as possible prime candidates in 831
771 brain injury [30], depression [31], anxiety [32], and cognitive a model of myocardial infarction in rats [36]. Furthermore, Q16 832
772 enhancement [33,34]. No peer reviewed study has been intravenous transplantation of exogenous mesenchymal 833
773 published to date in patients with Parkinson’s disease or stem cells was shown to protect mouse dopaminergic neu- 834
774 835
AD except a recent placebo-controlled clinical trial in de- rons against MPTP toxicity [37] and rat dopaminergic neu-
775 836
mentia patients [11]. However, in agreement with our find- rons against degeneration due to the proteasome inhibitor
776Q15 837
777 ings, a conclusive study on an AbPP transgenic mouse of MG-132 [38]. 838
778 AD suggests that transcranial LLLT is a potential candidate Alternative hypotheses to the actions of remote NIR 839
779 for treatment of AD [9]. include the modulation of immune cells and effects on 840
780 841
842 inflammatory mediators, such as the upregulation of anti- cytokines like IL-1, IL-4, IL-10, IL-11, or IL-13. As com- 903
843 inflammatory cytokines (IL-4, IL-10) [39]. plementary studies, a metabolomic analysis of caecal con- 904
844 tent, using proteomics and mass spectrometry, will help to 905
845 identify metabolic changes produced by NIR and particu- 906
3.3. Brain-gut axis and AD
846 907
larly bacterial byproducts, such as short-chain fatty acids
847 The contribution of gut microbiome also needs to be 908
and tryptophan, exerting a number of neuromodulatory
848 considered and leads to novel hypotheses about new possible 909
849 effects. For example, short-chain fatty acids have been 910
therapeutic approaches for AD treatment. First, a direct neu- shown to be produced by a number of GMB, such as Bifi-
850 911
ral communication occurs between the gut and the brain via dobacterium, Propionibacterium, Eubacterium, Lactoba-
851 912
852
the vagal nerve, as bacteria can stimulate afferent neurons of cillus, Clostridium, Roseburia, or Prevotella, promoting 913
853 the enteric nervous system [16]. Vagal signals from the gut the secretion of neurotransmitters and hormones and 914
854 could induce an anti-inflammatory reaction in a nicotinic reducing inflammation [51]. Better understanding of the 915
855 acetylcholine receptor a7 subunit–dependent manner [40]. mechanism underlying the effects of RGn500 treatment 916
856Q17 Furthermore, many metabolites have been reported to be will be possible by the 16SrRNA high-throughput gene 917
857 produced by gut bacteria that play an important role in the sequencing of GMB allowing the precise analysis of pre- 918
858 central nervous function not only such as GABA [41], sero- 919
sent bacterial communities [52] and possibly understanding
859 tonin [42], norepinephrine [43], acetylcholine [44], but also 920
the changes produced by the treatment. These studies will
860 indole-3-propionic acid [45], controlling inflammation 921
861 allow us to build a solid hypothesis supporting the testing 922
through interaction with GPR43 expressed on neutrophils of RGn500 in phase 2B trials.
862 923
and eosinophils [46].
863 924
864
Recent data have demonstrated the link between gut mi- 925
865 crobiota (GMB) and Parkinson’s disease as well as AD. 4. Conclusions 926
866 Alterations in the human microbiome have been shown 927
867 to represent a risk factor for Parkinson’s disease [47]. In Results obtained in the hereby study suggest that PBM 928
868 a mouse model of Parkinson’s disease, GMB have been may represent a novel nonpharmacological therapeutic 929
869 shown to be able to regulate motor deficits and neuroin- approach for the treatment of AD. The specific combination 930
870Q18 flammation [48]. Regarding AD, a recent article indicates of PBM/static magnetic field of the so-called emerging ther- 931
871 that an increase in the abundance of a pro-inflammatory apy we propose, including, furthermore, two application 932
872 GMB taxon, Escherichia/Shigella, and a reduction in the sites showing synergistic effects, points out very promising 933
873 abundance of an anti-inflammatory taxon E. rectale are results, considering especially the extremely severe pheno- 934
874 type of Ab25–35 mouse model of AD. Yet, a complex human 935
possibly associated with a peripheral inflammatory state
875 936
in patients with cognitive impairment and brain amyloid- disease such as AD cannot be fully recapitulated in this
876 937
osis [49]. This finding leads to the hypothesis that the context. Replicating this alleviated AD phenotype in other
877 938
878 GMB composition may drive peripheral inflammation, preclinical models will be our next step to support clinical 939
879 contributing to brain amyloidosis and, possibly, neurode- investigations. It is however worthy of note to acknowledge 940
880 generation and cognitive symptoms in AD. Conversely, a that multiple studies have demonstrated that transcranial 941
881 recent study demonstrated that a 12-week probiotic supple- PBM is safe and well tolerated [7,53–55] and clinical 942
882 ment positively affected cognitive functions and some investigations have been already reported [10,12]. Finally, 943
883 metabolic statuses in AD patients [50]. It might be possible the hypothesis that a dual mechanism of action is involved 944
884 that the stimulation of the abdomen could change the mi- opens new perspectives for the treatment of AD by 945
885 crobiota with the release of unknown factors producing a widening the therapeutic approach limited up to now by a 946
886 too reductionistic logic. 947
neuroprotective action on the brain.
887 948
888 949
889 3.4. Future directions 950
Acknowledgments
890 951
Future studies will be needed to explore various lines of
891 The authors thank Dr Patrick Lemoine for his constant sup- 952
892 research to test the hypothesis of a dual mechanism under- 953
port from the beginning of the project and for his valuable
893 lying the systemic response to NIR treatment and describe 954
advice.
894 its nature. Novel data are being generated in partnership 955
895 with Fresnel Institute (CNRS/Aix Marseille University) 956
896 aiming at elucidating the interaction of photonic and mag- 957
Supplementary data
897 netic exposure with neurons. Furthermore, we plan to 958
898 devote a particular interest to circulating mediators of Supplementary data related to this article can be found at 959
899 inflammation and more particularly to anti-inflammatory https://doi.org/10.1016/j.trci.2017.12.003. 960
900 961
901 962
902 963
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