PMID- 32922141
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200928
IS  - 1319-0164 (Print)
IS  - 2213-7475 (Electronic)
IS  - 1319-0164 (Linking)
VI  - 28
IP  - 9
DP  - 2020 Sep
TI  - Aliskiren, tadalafil, and cinnamaldehyde alleviate joint destruction biomarkers; 
      MMP-3 and RANKL; in complete Freund's adjuvant arthritis model: Downregulation of 
      IL-6/JAK2/STAT3 signaling pathway.
PG  - 1101-1111
LID - 10.1016/j.jsps.2020.07.011 [doi]
AB  - Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, which is 
      accompanied by progressive joint damage and disability. The intolerability of 
      conventional antirheumatic drugs by some patients necessitates the search for 
      effective antirheumatic agents having better tolerability. In the current work, 
      we aimed to investigate the efficacy of cinnamaldehyde, tadalafil, and aliskiren 
      as potential antirheumatic candidates and to explore their modulatory effects on 
      joint destruction, inflammatory response, and intracellular signaling. Arthritis 
      was induced in female Wistar rats by complete Freund's adjuvant (CFA) 0.4 ml s.c. 
      on days 1, 4, and 7. Treated groups received their respective drugs, starting 
      from day 13, daily for 3 weeks. Methotrexate and prednisolone were the standard 
      antirheumatic drugs, while cinnamaldehyde, tadalafil, and aliskiren were the test 
      agents. Treatment with cinnamaldehyde, tadalafil, or aliskiren reduced serum 
      levels of rheumatoid factor, and pro-inflammatory cytokines; tumor necrosis 
      factor-alpha and interleukin-6 (IL-6), along with elevated level of IL-10 which 
      is an anti-inflammatory cytokine. Besides, cartilage and bone destruction 
      biomarkers; matrix metalloproteinase-3 (MMP-3) and receptor activator of nuclear 
      factor-kappa B ligand (RANKL); were significantly reduced after treatment with 
      the test agents, which was further confirmed by histopathological investigation. 
      The elevated protein expressions of phosphorylated-Janus kinase 2 (p-JAK2), 
      phosphorylated-signal transducer and activator of transcription 3 (p-STAT3), and 
      inducible nitric oxide synthase (iNOS) in articular tissue were markedly 
      attenuated after treatment with cinnamaldehyde, tadalafil, or aliskiren, while 
      that of endothelial nitric oxide synthase (eNOS) was greatly enhanced. In 
      addition, oxidative stress and inflammatory markers such as malondialdehyde, 
      nitric oxide, and myeloperoxidase were reduced in joint tissue after treatment 
      with the test agents, while glutathione content was elevated. Furthermore, the 
      renin inhibitor aliskiren produced effects close to those of the normal and 
      methotrexate, the gold standard antirheumatic drug, in most of the measured 
      parameters. Collectively, these findings led to the assumption that the 
      downregulation of IL-6/JAK2/STAT3 signaling by cinnamaldehyde, tadalafil, and 
      aliskiren could alleviate joint destruction by MMP-3 and RANKL, reduce iNOS, and 
      enhance eNOS expressions. Moreover, aliskiren could be a promising therapeutic 
      agent for RA, because of its ability to normalize most of the measured parameters 
      after CFA-induced arthritis.
CI  - (c) 2020 The Author(s).
FAU - Azouz, Amany A
AU  - Azouz AA
AD  - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef 
      University, Beni-Suef 62514, Egypt.
FAU - Saleh, Esraa
AU  - Saleh E
AD  - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef 
      University, Beni-Suef 62514, Egypt.
AD  - Operations Pharmacy, General Fayoum Hospital, Fayoum, Egypt.
FAU - Abo-Saif, Ali A
AU  - Abo-Saif AA
AD  - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Nahda University, 
      Beni-Suef, Egypt.
LA  - eng
PT  - Journal Article
DEP - 20200803
PL  - Saudi Arabia
TA  - Saudi Pharm J
JT  - Saudi pharmaceutical journal : SPJ : the official publication of the Saudi 
      Pharmaceutical Society
JID - 9705695
PMC - PMC7474170
OTO - NOTNLM
OT  - Aliskiren
OT  - CFA, complete Freund's adjuvant
OT  - CFA-induced arthritis
OT  - DMARD, disease-modifying antirheumatic drug
OT  - GSH, reduced glutathione
OT  - H&E, hematoxylin and eosin
OT  - IL-10, interleukin-10
OT  - IL-6, interleukin-6
OT  - IL-6/JAK2/STAT3 signaling
OT  - JAK2, Janus kinase 2
OT  - MDA, malondialdehyde
OT  - MMP-3
OT  - MMP-3, matrix metalloproteinase-3
OT  - MPO, myeloperoxidase
OT  - NO, nitric oxide
OT  - PDE, phosphodiesterase
OT  - RA, rheumatoid arthritis
OT  - RANKL
OT  - RANKL, receptor activator of nuclear factor-kappa B ligand
OT  - RAS, renin angiotensin system
OT  - STAT3, signal transducer and activator of transcription 3
OT  - TNF-alpha, tumor necrosis factor-alpha
OT  - eNOS, endothelial nitric oxide synthase
OT  - iNOS, inducible nitric oxide synthase
COIS- The authors declare that they have no known competing financial interests or 
      personal relationships that could have appeared to influence the work reported in 
      this paper.
EDAT- 2020/09/15 06:00
MHDA- 2020/09/15 06:01
PMCR- 2020/08/03
CRDT- 2020/09/14 05:49
PHST- 2020/05/08 00:00 [received]
PHST- 2020/07/28 00:00 [accepted]
PHST- 2020/09/14 05:49 [entrez]
PHST- 2020/09/15 06:00 [pubmed]
PHST- 2020/09/15 06:01 [medline]
PHST- 2020/08/03 00:00 [pmc-release]
AID - S1319-0164(20)30170-5 [pii]
AID - 10.1016/j.jsps.2020.07.011 [doi]
PST - ppublish
SO  - Saudi Pharm J. 2020 Sep;28(9):1101-1111. doi: 10.1016/j.jsps.2020.07.011. Epub 
      2020 Aug 3.