PMID- 30825431
OWN - NLM
STAT- MEDLINE
DCOM- 20200108
LR  - 20201231
IS  - 1873-2968 (Electronic)
IS  - 0006-2952 (Linking)
VI  - 163
DP  - 2019 May
TI  - Cannabinoid derivatives acting as dual PPARgamma/CB2 agonists as therapeutic agents 
      for systemic sclerosis.
PG  - 321-334
LID - S0006-2952(19)30077-2 [pii]
LID - 10.1016/j.bcp.2019.02.029 [doi]
AB  - The endocannabinoid system (ECS) may play a role in the pathophysiology of 
      systemic sclerosis (SSc). Cannabinoids acting as dual PPARgamma/CB(2) agonists, such 
      as VCE-004.8 and Ajulemic acid (AjA), have been shown to alleviate skin fibrosis 
      and inflammation in SSc models. Since both compounds are being tested in humans, 
      we compared their activities in the bleomycin (BLM) SSc model. Specifically, the 
      pharmacotranscriptomic signature of the compounds was determined by RNA-Seq 
      changes in the skin of BLM mice treated orally with AjA or EHP-101, a lipidic 
      formulation of VCE-004.8. While both compounds down-regulated the expression of 
      genes involved in the inflammatory and fibrotic components of the disease and the 
      pharmacotranscriptomic signatures were similar for both compounds in some 
      pathways, we found key differences between the compounds in vasculogenesis. 
      Additionally, we found 28 specific genes with translation potential by comparing 
      with a list of human scleroderma genes. Immunohistochemical analysis revealed 
      that both compounds prevented fibrosis, collagen accumulation and Tenascin C 
      (TNC) expression. The endothelial CD31(+)/CD34(+) cells and telocytes were 
      reduced in BLM mice and restored only by EHP-101 treatment. Finally, differences 
      were found in plasmatic biomarker analysis; EHP-101, but not AjA, enhanced the 
      expression of some factors related to angiogenesis and vasculogenesis. Altogether 
      the results indicate that dual PPARgamma/CB2 agonists qualify as a novel therapeutic 
      approach for the treatment of SSc and other fibrotic diseases. EHP-101 
      demonstrated unique mechanisms of action related to the pathophysiology of SSc 
      that could be beneficial in the treatment of this complex disease without current 
      therapeutic options.
CI  - Copyright (c) 2019 Elsevier Inc. All rights reserved.
FAU - Garcia-Martin, Adela
AU  - Garcia-Martin A
AD  - Emerald Health Biotechnology Espana, Cordoba, Spain.
FAU - Garrido-Rodriguez, Martin
AU  - Garrido-Rodriguez M
AD  - Innohealth Group, Madrid, Spain.
FAU - Navarrete, Carmen
AU  - Navarrete C
AD  - Emerald Health Pharmaceuticals, San Diego, CA, USA.
FAU - Caprioglio, Diego
AU  - Caprioglio D
AD  - Dipartimento di Scienze del Farmaco, Universita del Piemonte Orientale, Novara, 
      Italy.
FAU - Palomares, Belen
AU  - Palomares B
AD  - Maimonides Biomedical Research Institute of Cordoba, Spain; Departament of 
      Cellular Biology, Physiology and Immunology, University of Cordoba, Spain; 
      Universitary Hospital Reina Sofia, Cordoba, Spain.
FAU - DeMesa, Jim
AU  - DeMesa J
AD  - Emerald Health Pharmaceuticals, San Diego, CA, USA.
FAU - Rollland, Alain
AU  - Rollland A
AD  - Emerald Health Pharmaceuticals, San Diego, CA, USA.
FAU - Appendino, Giovanni
AU  - Appendino G
AD  - Dipartimento di Scienze del Farmaco, Universita del Piemonte Orientale, Novara, 
      Italy.
FAU - Munoz, Eduardo
AU  - Munoz E
AD  - Maimonides Biomedical Research Institute of Cordoba, Spain; Departament of 
      Cellular Biology, Physiology and Immunology, University of Cordoba, Spain; 
      Universitary Hospital Reina Sofia, Cordoba, Spain. Electronic address: 
      fi1muble@uco.es.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190227
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Biomarkers)
RN  - 0 (Cannabinoids)
RN  - 0 (Hydroquinones)
RN  - 0 (PPAR gamma)
RN  - 0 (Receptor, Cannabinoid, CB2)
RN  - 11056-06-7 (Bleomycin)
RN  - 7J8897W37S (Dronabinol)
RN  - OGN7X90BT8 (lenabasum)
SB  - IM
MH  - Animals
MH  - Biomarkers
MH  - Bleomycin/toxicity
MH  - Cannabinoids/*pharmacology
MH  - Dronabinol/administration & dosage/*analogs & derivatives/pharmacology
MH  - Female
MH  - Fibrosis/chemically induced
MH  - Gene Expression Regulation/*drug effects
MH  - Hydroquinones/administration & dosage/*pharmacology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - PPAR gamma/*agonists/genetics/metabolism
MH  - Pulmonary Fibrosis
MH  - Receptor, Cannabinoid, CB2/*agonists/genetics/metabolism
MH  - Scleroderma, Systemic/*drug therapy
MH  - Skin/drug effects/pathology
OTO - NOTNLM
OT  - Bleomycin
OT  - Cannabinoids
OT  - Inflammation
OT  - Systemic fibrosis
OT  - Transcriptomic signature
OT  - Vasculopathy
EDAT- 2019/03/03 06:00
MHDA- 2020/01/09 06:00
CRDT- 2019/03/03 06:00
PHST- 2019/01/16 00:00 [received]
PHST- 2019/02/26 00:00 [accepted]
PHST- 2019/03/03 06:00 [pubmed]
PHST- 2020/01/09 06:00 [medline]
PHST- 2019/03/03 06:00 [entrez]
AID - S0006-2952(19)30077-2 [pii]
AID - 10.1016/j.bcp.2019.02.029 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2019 May;163:321-334. doi: 10.1016/j.bcp.2019.02.029. Epub 
      2019 Feb 27.