In vitro effect of a synthesized sulfonamido-based gallate on articular chondrocyte metabolism

Lin, Xiao; Zheng, Li; Liu, Qin; Liu, Buming; Jiang, Bingli; Peng, Xiaoyu; Lin, Cui-Wu

doi:10.1016/j.bmcl.2014.04.015

Cited by 10 publications

(9 citation statements)

References 20 publications

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“…However, GA has much weaker anti-oxidant effects than its esters and inferior bioactivity, which may be due to its hydrophilicity. It was hypothesized that synthetic compounds of gallates and sulfonamides may enhance its chondro-protective and pharmacological effects, Our previous studies demonstrated the chondro-protective effects of sulfonamido-based gallate [ 15 – 18 ]. But pharmacological effects, especially the effects on OA were still unknown.…”

Section: Discussionmentioning

confidence: 99%

“…However, another study showed that sulfonamides were slightly cytotoxic in human keratinocytes and rat hepatocytes [ 37 ]. Furthermore, recent studies indicated that sulfonamide-based gallates effectively inhibited IL-1β induced osteoarthritis [ 14 ] and exerted effects on cartilage growth [ 15 – 18 ]. In this study, JEZ-C, as a novel derivative of GA, can better support the chondrocyte growth and maintain their phenotype than its sources, as evidenced by increased cell proliferation, upregulated cartilage specific matrix compared with GA and SMZ.…”

Section: Discussionmentioning

confidence: 99%

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

Wei

Zou

et al. 2015

PLoS ONE

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Wei

Zou

et al. 2015

PLoS ONE

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“…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.…”

Section: Discussionmentioning

confidence: 64%

“…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.…”

Section: Introductionmentioning

confidence: 79%

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

et al. 2016

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Gallic acid (GA) and its derivatives are anti-inflammatory agents and are reported to have potent effects on Osteoarthritis (OA) treatment. Nonetheless, it is generally accepted that the therapeutic effect and biocompatibility of GA is much weaker than its esters due to the high hydrophilicity. The therapeutic effect of GA on OA could be improved if certain structural modifications were made to increase its hydrophobicity. In this study, a novel sulfonamido-based gallate was synthesized by bonding sulfonamide with GA, and its biological evaluations on OA were investigated. Results show that 5-[4-(Pyrimidin-2-ylsulfamoylphenyl)]-carbamoyl-benzene-1,2,3-triyl triacetate (HAMDC) was able to reverse the effects induced by Interleukin-1 (IL-1) stimulation, and it also had a great effect on chondro-protection via promoting cell proliferation and maintaining the phenotype of articular chondrocytes, as well as enhancing synthesis of cartilage specific markers such as aggrecan, collagen II and Sox9. Furthermore, a docking study showed that HAMDC fits into the core of the active site of a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), which provides an explanation for its activity and selectivity.

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“…2C). Our previous study showed that GA derivatives had stronger anti-oxidant effects than GA [29][30][31][32][33]55], which may be due to that GA is much more hydrophilic and cytotoxic than its esters [14].…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

A Novel Synthesized Sulfonamido-Based Gallate-JEZTC Blocks Cartilage Degradation on Rabbit Model of Osteoarthritis: An in Vitro and in Vivo Study

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: 3, 4, 5-trihydroxy-N-{4-[(5-methylisoxazol-3-yl) sulfamoyl] phenyl} benzamide (JEZTC), synthesized from gallic acid (GA) and sulfamethoxazole (SMZ), was reported with chondroprotective effects. However, the effects of JEZTC on osteoarthritis (OA) are still unclear. The goal of this study was to investigate the anti-osteoarthritic properties of JEZTC on interleukin-1-beta (IL-1β) stimulated chondrocytes in vitro and a rabbit anterior cruciate ligament transaction (ACLT) OA model in vivo. Methods: Changes in matrix metalloproteinases (MMPs) and apoptosis genes (bax, caspase 3 and tnf-α) and OA-specific protein (MMP-1) expression in vitro and in vivo were detected by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemistry. The production of reactive oxygen species (ROS) were investigated upon the treatment of JEZTC in chondrocytes processed with IL-1β in vitro and OA in vivo. Effect of JEZTC on OA was further studied by the macroscopic and histological evaluation and scores. The key proteins in signaling pathways inMAPK/P38, PI3KAkt and NF-κB also determined using western blot (WB) analysis. Results: JEZTC could significantly suppress the expression of MMPs and intracellular ROS, while meaningfully increase the gene expression of tissue inhibitor of metalloproteinase-1 (TIMP-1). Moreover, there was less cartilage degradation in JEZTC group compared with the phosphate-buffered saline (PBS) group in vivo. Results also indicated that JEZTC exerts effect on OA by regulating MAPKs and PI3K/Akt signaling pathways to activate NF-κB pathway, leading to the down-regulation of MMPs. The chondro-protective effect of JEZTC may be related with its ability to inhibit chondrocyte apoptosis by reduction of ROS production. Conclusion: JEZTC may be a possible therapeutic agent in the treatment of OA.

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In vitro effect of a synthesized sulfonamido-based gallate on articular chondrocyte metabolism

Cited by 10 publications

References 20 publications

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

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

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

A Novel Synthesized Sulfonamido-Based Gallate-JEZTC Blocks Cartilage Degradation on Rabbit Model of Osteoarthritis: An in Vitro and in Vivo Study

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