Synoviolin (Syvn1), a RING-type E3 ubiquitin ligase in endoplasmic reticulum associated protein degradation, is involved in rheumatoid arthritis, fibrosis, liver cirrhosis and obesity. LS-102 inhibited the autoubiquitination of synoviolin with an IC50 value of 20 μM. Further evaluation of LS-102 in an in vitro ubiquitination assay showed that the inhibition of synoviolin activity by LS-102 was dose-dependent with an IC50 value of 35 μM. LS-102 inhibited HeLa cell growth at very high concentrations with an IC50 of 32.7 μM. Moreover, treatment of RSCs (rheumatoid synovial cells) with LS-102 suppressed synovial cell growth dose-dependently and with much greater potency than that observed in HeLa cells. In a mouse model of arthritis, intraperitoneal treatment with 1.3 mg/kg or 4.0 mg/kg LS-102 starting on day 21 reduced the clinical severity scores compared to vehicle controls. Finally, histological analysis showed lower histological arthritis scores in mice treated with LS-102 compared with wild-type mice[2].
LS-102 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Adipose stem cells (HFD-ASCs)
10 µg/mL, 20 µg/mL, 30 µg/mL, 40 µg/mL
6 hours, 12 hours, 24 hours, 48 hours
LS-102 significantly inhibited the secretion of TNF-α and PAI-1 by adipose stem cells in a concentration-dependent manner (P < 0.05).
Drug Des Devel Ther. 2022 Mar 14;16:647-664
Adipose stem cells (ND-ASCs)
10 µg/mL, 20 µg/mL, 30 µg/mL, 40 µg/mL
6 hours, 12 hours, 24 hours, 48 hours
LS-102 significantly inhibited the secretion of TNF-α and PAI-1 by adipose stem cells in a concentration-dependent manner (P < 0.05).
Drug Des Devel Ther. 2022 Mar 14;16:647-664
H9c2 cells
0.3125, 0.625, 1.25 µM
24 hours
To investigate the protective effect of LS-102 on H9c2 cells against hypoxia/reoxygenation (H/R) injury. Results showed that LS-102 significantly increased cell viability, reduced apoptosis, decreased levels of ROS, CK, LDH, and calcium, and upregulated mitochondrial membrane potential (MMP) and Bax/Bcl-2 ratio.
Front Pharmacol. 2020 Sep 17;11:1083
LS-102 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
C57BL/6J mice
Intraperitoneal injection
50 mg/kg
Once daily for 2 months
To evaluate the effect of LS-102 on weight gain and white adipose tissue accumulation
EMBO J. 2015 Apr 15;34(8):1042-55
AG6 mice
DENV2 infection model
Intraperitoneal injection
15 mg/kg
Daily for 7 days
Evaluate the effect of LS-102 on DENV2 infection
Proc Natl Acad Sci U S A. 2024 Apr 16;121(16):e2317978121
C57BL/6J mice
High-fat diet-induced obesity-related nephropathy model
Intragastric administration
10 mg/kg, 40 mg/kg
Once daily for 4 weeks
LS-102 significantly improved perirenal adipose tissue inflammation and renal pathological changes in obesity-related nephropathy model mice and inhibited the TGF-β1/Smad signaling cascade.
Drug Des Devel Ther. 2022 Mar 14;16:647-664
Sprague-Dawley rats
Myocardial ischemia/reperfusion (I/R) injury model
Oral
2.5, 5, 10 mg/kg
Single administration, lasting 30 min ischemia and 90 min reperfusion
To evaluate the protective effect of LS-102 on myocardial I/R injury in rats. Results showed that LS-102 significantly reduced myocardial infarct size, decreased serum CK-MB and LDH activities, improved ECG parameters and hemodynamics, and reduced the incidence of arrhythmia.
Front Pharmacol. 2020 Sep 17;11:1083
Zebrafish embryos
Zebrafish embryo model
Administration in water
27.8, 83.3, 250 µg/ml
24 hours
LS-102 significantly ameliorated astemizole-induced heart rate slowing, increased SV-BA spacing, and prevented arachidonic acid-induced thrombosis in zebrafish
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