A Novel Synthesized Sulfonamido-Based Gallate—JEZ-C as Potential Therapeutic Agents for Osteoarthritis

Abstract

Gallic acid (GA) and its derivatives are anti-inflammatory agents reported to have an effect on osteoarthritis (OA). However, GA has much weaker anti-oxidant effects and inferior bioactivity compared with its derivatives. We modified GA with the introduction of sulfonamide to synthesize a novel compound named JEZ-C and analyzed its anti-arthritis and chondro-protective effects. Comparison of JEZ-C with its sources i.e. GA and Sulfamethoxazole (SMZ) was also performed. Results showed that JEZ-C could effectively inhibit the IL-1-mediated induction of MMP-1 and MMP-13 and could induce the expression of TIMP-1, which demonstrated its ability to reduce the progression of OA. JEZ-C can also exert chondro-protective effects by promoting cell proliferation and maintaining the phenotype of articular chondrocytes, as evidenced by improved cell growth, enhanced synthesis of cartilage specific markers such as aggrecan, collagen II and Sox9. Meanwhile, expression of the collagen I gene was effectively downregulated, revealing the inhibition of chondrocytes dedifferentiation by JEZ-C. Hypertrophy that may lead to chondrocyte ossification was also undetectable in JEZ-C groups. The recommended dose of JEZ-C ranges from 6.25×10-7 μg/ml to 6.25×10-5 μg/ml, among which the most profound response was observed with 6.25×10-6 μg/ml. In contrast, its source products of GA and SMZ have a weak effect not only in the inhibition of OA but also in the bioactivity of chondrocytes, which indicated the significance of this modification. This study revealed JEZ-C as a promising novel agent in the treatment of chondral and osteochondral lesions.

Exosomes derived from platelet-rich plasma present a novel potential in alleviating knee osteoarthritis by promoting proliferation and inhibiting apoptosis of chondrocyte via Wnt/β-catenin signaling pathway

“…Finally, the cell nuclei were counterstained with DAPI (1:5000; Beyotime; Cat. #C1002) and observed with confocal microscopy (Olympus, Tokyo, Japan, BX61W1-FV1000) [53].…”

“…Then, 100 μL of cell suspension was added into 5 mL of fluid and mixed with 5 μL of annexin V/PE and 10 μL of 7-AAD. Afterwards, the sample was gently mixed at 4 °C under darkness for 15 min and analyzed by flow cytometr y[53] within 1 h of being added to 400 μL of 1× Binding Buffer.…”

“…All rabbits were randomly divided into four groups: (1) control group (without surgery; received normal saline by intra-articular(IA) injection once a week, n = 6); (2) OA model group (with surgery; received normal saline by intra-articular injection once a week, n = 6); (3) OA + PRP-Exos group (with surgery; received 100 μg/mL PRP-Exos by intra-articular injection once a week, n = 6); and (4) OA + PRP-As group (with surgery; received 100 μg/mL PRP by intra-articular injection once a week, n = 6). The OA model rabbits were anaesthetized by injection of 10% chloral hydrate (4 mL/kg) and underwent surgery of left knee, in which the medial collateral ligament and the anterior cruciate ligament (ACL) were cut off and the medial meniscus was excised [1, 53, 59]. After surgery, penicillin potassium (8 million U/kg, Shandong Lukang Biotechnology, China) was used to prevent infection by intramuscular injection for 7 days.…”

Synthesis, Biological Evaluation, and Docking Studies of a Novel Sulfonamido-Based Gallate as Pro-Chondrogenic Agent for the Treatment of Cartilage

“…However, it exhibited an inhibitive effect on chondrocytes growth in the concentration between 0 and 40 μg/mL in a cytotoxicity assay, and therefore the subsequent experiments were not performed in this way. Nevertheless, other synthesized sulfonamido-based gallate analogues we had investigated previously [ 26 , 27 , 28 , 29 , 30 ] presented great effect on promoting chondrocyte growth and upregulating the expression of aggrecan, collagen II and Sox9, which confirm the fact that coupling of the phenyl ring with the sulfonamide group is critical for the pro-chondrogenic activity of these compounds and this docking model would provide us with a quick method to screen out the effective compounds. More docking studies should be performed in our further investigation to optimize their structures.…”

“…Recently, we have reported a series of synthesized sulfonamido-based gallates and their effectiveness on chondro-protection [ 26 , 27 , 28 , 29 , 30 ], which confirm the fact that coupling of the phenyl ring with the sulfonamide group is critical for the activity of preventing cartilage degeneration. Herein, another analog was synthesized and shown to be effective in biological evaluation, a docking study was therefore performed to provide an explanation for its activity and selectivity.…”