PMID- 30076848
OWN - NLM
STAT- MEDLINE
DCOM- 20190708
LR  - 20190708
IS  - 1873-2968 (Electronic)
IS  - 0006-2952 (Linking)
VI  - 157
DP  - 2018 Nov
TI  - EHP-101, an oral formulation of the cannabidiol aminoquinone VCE-004.8, 
      alleviates bleomycin-induced skin and lung fibrosis.
PG  - 304-313
LID - S0006-2952(18)30317-4 [pii]
LID - 10.1016/j.bcp.2018.07.047 [doi]
AB  - Systemic sclerosis (SSc) or scleroderma is a chronic multi-organ autoimmune 
      disease characterized by vascular, immunological, and fibrotic abnormalities. The 
      etiology of SSc is unknown, but there is growing evidence that dysfunction of the 
      endocannabinoid system (ECS) plays a critical role in its development. Since the 
      semi-synthetic cannabinoquinoid VCE-004.8 could alleviate bleomycin (BLM)-induced 
      skin fibrosis, we have investigated an oral lipid formulation (EHP-101) of this 
      dual PPARgamma/CB(2) receptors activator for the prevention of skin- and lung 
      fibrosis and of collagen accumulation in BLM challenged mice. 
      Immunohistochemistry analysis of the skin showed that EHP-101 could prevent 
      macrophage infiltration as well as the expression of Tenascin C (TNC), vascular 
      cell adhesion molecule 1 (VCAM1), and the alpha-smooth muscle actin (SMA). EHP-101 
      could also prevent the reduced expression of vascular CD31 typical of skin 
      fibrosis. RNAseq analysis of skin biopsies showed a clear effect of EHP-101 in 
      the inflammatory and epithelial-mesenchymal transition transcriptomic signatures. 
      TGF-beta-regulated genes [matrix metalloproteinase-3 (Mmp3), cytochrome b-245 heavy 
      chain (Cybb), lymphocyte antigen 6E (Ly6e), vascular cell adhesion molecule-1 
      (Vcam1) and Integrin alpha-5 (Itga5)] were induced in BLM mice and repressed by 
      EHP-101 treatment. By intersecting differentially expressed genes in 
      EHP-101-treated mice with a dataset of human scleroderma intrinsic genes, 53 
      overlapped genes were discovered, including biomarkers of SSc like the C-C motif 
      chemokine 2 (Ccl2) and the interleukin 13 receptor subunit alpha 1 (IL-13Ra1) 
      genes. Taken together, these data provide a rationale for further developing 
      VCE-004.8 as an orally active agent to alleviate scleroderma and, possibly, other 
      fibrotic diseases as well.
CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
FAU - Garcia-Martin, Adela
AU  - Garcia-Martin A
AD  - Vivacell Biotechnology Espana, Cordoba, Spain.
FAU - Garrido-Rodriguez, Martin
AU  - Garrido-Rodriguez M
AD  - Innohealth Group, Madrid, Spain.
FAU - Navarrete, Carmen
AU  - Navarrete C
AD  - Vivacell Biotechnology Espana, Cordoba, Spain.
FAU - Del Rio, Carmen
AU  - Del Rio C
AD  - Instituto Maimonides de Investigacion Biomedica de Cordoba (IMIBIC), Cordoba, 
      Spain; Departamento de Biologia Celular, Fisiologia e Inmunologia, Universidad de 
      Cordoba, Cordoba, Spain; Hospital Universitario Reina Sofia, Cordoba, Spain.
FAU - Bellido, Maria L
AU  - Bellido ML
AD  - Vivacell Biotechnology Espana, Cordoba, Spain; Emerald Health Pharmaceuticals, 
      San Diego, USA.
FAU - Appendino, Giovanni
AU  - Appendino G
AD  - Dipartimento di Scienze del Farmaco, Universita del Piemonte Orientale, Novara, 
      Italy.
FAU - Calzado, Marco A
AU  - Calzado MA
AD  - Instituto Maimonides de Investigacion Biomedica de Cordoba (IMIBIC), Cordoba, 
      Spain; Departamento de Biologia Celular, Fisiologia e Inmunologia, Universidad de 
      Cordoba, Cordoba, Spain; Hospital Universitario Reina Sofia, Cordoba, Spain.
FAU - Munoz, Eduardo
AU  - Munoz E
AD  - Instituto Maimonides de Investigacion Biomedica de Cordoba (IMIBIC), Cordoba, 
      Spain; Departamento de Biologia Celular, Fisiologia e Inmunologia, Universidad de 
      Cordoba, Cordoba, Spain; Hospital Universitario Reina Sofia, Cordoba, Spain. 
      Electronic address: fi1muble@uco.es.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180802
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Quinones)
RN  - 11056-06-7 (Bleomycin)
RN  - 19GBJ60SN5 (Cannabidiol)
RN  - 9007-34-5 (Collagen)
SB  - IM
MH  - Administration, Oral
MH  - Animals
MH  - Bleomycin
MH  - Blood Vessels/drug effects
MH  - Cannabidiol/*analogs & derivatives
MH  - Collagen/analysis
MH  - Female
MH  - Fibrosis
MH  - Lung/drug effects/*pathology
MH  - Mice, Inbred BALB C
MH  - Phenotype
MH  - Quinones/administration & dosage/therapeutic use
MH  - Skin/blood supply/drug effects/metabolism/*pathology
MH  - Transcriptome/drug effects
OTO - NOTNLM
OT  - Bleomycin
OT  - Cannabinoids
OT  - Inflammation
OT  - Systemic fibrosis
OT  - Transcriptomic signature
EDAT- 2018/08/05 06:00
MHDA- 2019/07/10 06:00
CRDT- 2018/08/05 06:00
PHST- 2018/06/09 00:00 [received]
PHST- 2018/07/31 00:00 [accepted]
PHST- 2018/08/05 06:00 [pubmed]
PHST- 2019/07/10 06:00 [medline]
PHST- 2018/08/05 06:00 [entrez]
AID - S0006-2952(18)30317-4 [pii]
AID - 10.1016/j.bcp.2018.07.047 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2018 Nov;157:304-313. doi: 10.1016/j.bcp.2018.07.047. Epub 
      2018 Aug 2.