Swainsonine inhibits proliferation and collagen synthesis of NIH-3T3 cells by declining miR-21

Abstract

Swainsonine (SW) is an indolizidine alkaloid first discovered in Swainsona canescens. This study explored the effects of SW on mouse embryo fibroblast NIH-3T3 cell proliferation and collagen synthesis, as well as potential molecule mechanisms. We discovered that SW exposure lowered the viability and proliferation of NIH-3T3 cells. The collagen synthesis was reduced after SW exposure, as evidenced by declines of the mRNA and protein levels of collagen I (CoI I), collagen III (CoI III) and a-smooth muscle actin (a-SMA) in NIH-3T3 cells, as well as reduction of collagen concentration in the culture supernatant of NIH-3T3 cells. Mechanically, transforming growth factor b1 (TGF-b1) stimulation elevated the microRNA-21 (miR-21) expression in NIH-3T3 cells. SW reversed the TGF-b1-caused elevation of miR-21. Up-regulation of miR-21 attenuated the inhibitory influences of SW on NIH-3T3 cell viability, proliferation and collagen synthesis. Silence of miR-21 had converse influence. Besides, SW inactivated PI3K/AKT and NF-jB pathways via declining miR-21. Altogether, SW inhibited the proliferation and collagen synthesis of fibroblast NIH-3T3 might be through declining miR-21 and then suppressing PI3K/AKT and NF-jB pathways. SW may be an effective therapeutic medicine for scar hyperplasia.

Intracellular signaling dynamics and their role in coordinating tissue repair

“…NFAT transcription factors exist in an inactive state in the cytosol and upon activation, the transcription factors translocate to the nucleus and begin gene transcription (Aramburu et al, ; Fisher, Yang, Medikonduri, & Jafri, ; Loh et al, ) allowing NFAT to translocate to the nucleus. The main injury repair pathways linked to NFAT in fibroblasts are related to cellular proliferation (Neal & Clipstone, ; Senavirathna et al, ) and ECM production (Cobbs & Gooch, ; Dooley et al, ; C. Li, Wang, Fu, Li, & Li, ; Stanisavljevic, Porta‐de‐la‐Riva, Batlle, de Herreros, & Baulida, ; Zimmerman et al, ). In regard to proliferation, a constitutive NFATc1‐mutant NIH 3T3‐L1 fibroblast line had an increased proliferation rate compared to naïve NIH 3T3 cells, and the NFATc1 mutant proliferation was insensitive to changes in serum levels, unlike naïve 3T3s (Neal & Clipstone, ).…”

“…NFAT transcription factors exist in an inactive state in the cytosol and upon activation, the transcription factors translocate to the nucleus and begin gene transcription (Aramburu et al, 1999;Fisher, Yang, Medikonduri, & Jafri, 2006;Loh et al, 1996) allowing NFAT to translocate to the nucleus. The main injury repair pathways linked to NFAT in fibroblasts are related to cellular proliferation (Neal & Clipstone, 2003;Senavirathna et al, 2018) and ECM production Dooley et al, 2010;C. Li, Wang, Fu, Li, & Li, 2019;Stanisavljevic, Porta-de-la-Riva, Batlle, de Herreros, & Baulida, 2011;Zimmerman et al, 2013).…”

Recent Developments in the Synthesis of Polyhydroxylated Indolizidines

“…[14] It effectively inhibits lysosomal α-mannosidase and mannosidase II [15][16] and exhibits anticancer, antimetastatic, antiproliferative, and immunoregulatory activity. [17][18][19][20][21][22][23][24][25] (À )-Swainsonine (2) has been a subject of several clinical trials as an antitumor drug, but further developments have been halted due to swainsonine side effects, despite initial positive results. [26][27][28] Unlike natural enantiomer, (+)-swainsonine (ent-2) is inactive towards mannosidases, but it is a good inhibitor of L-rhamnosidase.…”

“…The first one is a representative of trihydroxylated indolizidines and was first isolated from the fungus Rhizoctonia leguminicola , [12–13] later was found in several plants, including Swainsona canescens [14] . It effectively inhibits lysosomal α‐mannosidase and mannosidase II [15–16] and exhibits anticancer, antimetastatic, antiproliferative, and immunoregulatory activity [17–25] . (−)‐Swainsonine ( 2 ) has been a subject of several clinical trials as an antitumor drug, but further developments have been halted due to swainsonine side effects, despite initial positive results [26–28] .…”