In Vitro Study of Licorice on IL-1β-Induced Chondrocytes and In Silico Approach for Osteoarthritis

Abstract

Osteoarthritis (OA) is a common degenerative joint disorder that affects joint function, mobility, and pain. The release of proinflammatory cytokines stimulates matrix metalloproteinases (MMPs) and aggrecanase production which further induces articular cartilage degradation. Hypertrophy-like changes in chondrocytes are considered to be an important feature of OA pathogenesis. A Glycyrrhiza new variety, Wongam (WG), was developed by the Korea Rural Development Administration to enhance the cultivation and quality of Glycyrrhizae Radix et Rhizoma (licorice). This study examined the regulatory effect of WG against hypertrophy-like changes such as RUNX2, Collagen X, VEGFA, MMP-13 induction, and Collagen II reduction induced by IL-1β in SW1353 human chondrocytes. Additionally, in silico methods were performed to identify active compounds in licorice to target chondrocyte hypertrophy-related proteins. WG showed inhibitory effects against IL-1β-induced chondrocyte hypertrophy by regulating both HDAC4 activation via the PTH1R/PKA/PP2A pathway and the SOX9/β-catenin signaling pathway. In silico analysis demonstrated that 21 active compounds from licorice have binding potential with 11 targets related to chondrocyte hypertrophy. Further molecular docking analysis and in vivo studies elicited four compounds. Based on HPLC, isoliquiritigenin and its precursors were identified and quantified. Taken together, WG is a potential therapeutic agent for chondrocyte hypertrophy-like changes in OA.

Protein phosphatase 2A modulation and connection with miRNAs and natural products

“…Retinoic acid promotes ERK dephosphorylation by upregulating PP2A in T‐cell receptor/CD28‐stimulated natural killer cells 36 . Wongam, a licorice‐derived natural product, suppresses IL‐1beta‐promoted chondrocyte hypertrophy and nuclear translocation of histone deacetylase 4 (HDCA4), downregulated by PP2A inhibitor okadaic acid 37 . This result suggests that wongam upregulates PP2A (Table 1).…”

“…27 Theasaponin E1, a green tea seed-derived saponin, reduces neuroinflammation of neuroblastoma and glioblastoma cells by upregulating PP2A. 28 35 Hepatocytes Theasaponin E1 28 Neuroblastoma Retinoic acid 36 Natural killer cells α-Tocopherol succinate 29 Prostate ca Wongam 37…”

“…36 Wongam, a licoricederived natural product, suppresses IL-1beta-promoted chondrocyte hypertrophy and nuclear translocation of histone deacetylase 4 (HDCA4), downregulated by PP2A inhibitor okadaic acid. 37 This result suggests that wongam upregulates PP2A ( Granulocyte-macrophage Nodularin 49 Liver cells Ursolic acid 50 Heart Chaetomellic anhydride 51 7-Deoxy-okadaic acid 52 Dinophysistoxin-4 53 Hipposulfate C 54 Halisulfate-7 54 Irregularasulfate 54…”

“…The discovery of drugs that modulate PP2A may regulate several diseases and cancer developments 11 . Many natural products show PP2A‐modulating functions (activating 15–37 and inhibitory 38–54 ), but lack comprehensive organization (Figure 2), particularly for microRNA (miRNA) modulation and their targeting investigation. miRNAs are short, single‐strand, non‐coding RNAs (21–23 nt) that target specific genes to downregulate their expressions 55 .…”

Recent Advances in Glycyrrhiza glabra (Licorice)-Containing Herbs Alleviating Radiotherapy- and Chemotherapy-Induced Adverse Reactions in Cancer Treatment

“…More than 55% of patients suffer from pain during cancer treatment [162]. A previous study shows the ability of licorice to relieve pain in terminal cancer patients [163], and this may be due to the anti-inflammatory and antioxidative effects of licorice [164]. In chemotherapy treatment, paclitaxel is one of the most widely used chemotherapeutic drugs for several cancers.…”