INTERNATIONAL IMMUNOPHARMACOLOGY
·
2018
·
IF 3.118
Man Zhang,Yanqing Wu,Ling Xie,Chen-Huai Teng,Fang-Fang Wu,Ke-Bin Xu,Xiong Chen,Jian Xiao,Hong-Yu Zhang,Da-Qing Chen
Traumatic brain injury (TBI) caused by an external mechanical force acting on the brain is a serious neurological condition. Inflammation plays an important role in prolonging secondary tissue injury after TBI, leading to neuronal cell death and dysfunction. Isoliquiritigenin (ILG) is a flavonoid monomer with anti-inflammatory characteristic. Thus, we had investigated the potential protective effects of ILG on TBI-induced injuries and identified the mechanisms underlying it. Here, we have demonstrated that ILG preserves blood brain barrier (BBB) integrity in vivo, suppresses the activation of microglia and inflammatory responses in mice after TBI, consequently leading to neurofunctional deficits, brain oedema , structural damage, and macrophage infiltration. In vitro, ILG exerts anti-inflammatory effect, and upregulates tight junction proteins 120‑β‑catenin and occludin in SH‑SY5Y cells under oxygen glucose deprivation/reoxygenation (OGD/D) condition. Additionally, we found that PI3K/AKT/GSK‑3β signalling pathway is involved in ILG treatment for TBI. To further confirm it, we had used SC79 (ethyl 2‑amino‑6‑chloro‑4‑(1‑cyano‑2‑ethoxy‑2‑oxoethyl)‑4H‑chromene‑3‑carboxylate), an Akt specific activator, to activate Akt, we found that SC79 partially reduces the protective effect of ILG for TBI. Overall, our current study reveals the neuroprotective role of ILG on TBI-induced BBB damage, downregulated tight junction proteins via PI3K/AKT/GSK‑3β signalling pathway. Furthermore, ILG suppresses the secretion of pro-inflammatory cytokines after TBI through inhibiting the PI3K/AKT/GSK‑3β/NF‑κB signalling pathway. Our findings suggest that GSK‑3β is a key regulatory factor during TBI-induced secretion of inflammatory cytokines, neuronal apoptosis and destruction of BBB.
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SPECTROCHIMICA ACTA PART A-MOLECULAR AND BIOMOLECULAR SPECTROSCOPY
·
2025
·
IF 4.6
Xuewa Jiang,Shaoyan Yi,Pingping Shen,Richa Raj,Jian Zhang,Haixia Ge
Chronic low-grade inflammation, driven by elevated levels of circulating high mobility group box1 (HMGB1), plays a crucial role in the pathogenesis of multiple chronic diseases. Glycyrrhetinic acid (GA) and isoliquiritigenin (ISL) are representative metabolites in licorice, exhibit potent regulatory effects on HMGB1-mediated chronic inflammation. In this research, we investigated the interactions of GA and ISL with HMGB1 using multi-spectroscopy, surface plasmon resonance (SPR), and molecular docking. Fluorescence spectroscopy revealed that GA or ISL binds to HMGB1, leading to static fluorescence quenching of the protein. Additionally, the binding of GA or ISL altered the microenvironment of tryptophan and decreased the α-helix content of HMGB1 to varying extents. Dynamic light scattering (DLS) showed that GA induced aggregation of the HMGB1 complex into large particles, while ISL reduced the particle size of HMGB1. SPR analysis confirmed that GA and ISL bound reversibly to HMGB1 with K d values of 53.0 ± 3.6 and 16.3 ± 0.5 μM, respectively. Molecular docking further elucidated the binding modes and sites of GA and ISL on HMGB1, showing that GA binds to the B-box and ISL binds to the A-box of HMGB1, with hydrogen bonding and hydrophobic interactions as the primary driving forces. Isobologram analysis demonstrated that the combination of GA and ISL exhibited a significant synergistic inhibitory effect on HMGB1-induced inflammation on RAW264.7 cells, with an optimal combination ratio of 1:1. This study reveals that GA and ISL synergistically exert anti-inflammatory effect by modulating HMGB1 conformation, offering new insights into licorice extracts for preventing chronic inflammatory diseases.
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CURRENT MEDICINAL CHEMISTRY
·
2023
·
IF 4.1
Xu Cong,Zhang Cheng,Ganesan Kumar,Qui Chen,Tang Hailin,Gao Fei,Liu Qingqing,Wu Jianming,Sui Yue,Li Peng,Zhang Jinming,Chen Jianping
Introduction: Triple-negative breast cancer (TNBC), an aggressive type of
breast cancer, remains difficult to treat. Isoliquiritigenin (ISL) is a bioactive compound
that is insoluble in water and exhibits significant anti-TNBC activity. Method: We previously
prepared oral aqueous ISL@ZLH NPs; however, they were less stable in a freezing
environment. Hence, the present study aimed to improve the stability of ISL@ZLH
NPs using cryoprotectants that can withstand long storage times and are effective in TNBC
treatment by creating an efficient oral drug delivery system. Freeze-dried ISL@ZLH
NP powder was prepared by solvent evaporation, followed by the addition of trehalose
and sucrose. The freeze-dried ISL@ZLH NP pow was optimized and characterized. The
anti-TNBC efficacy and pharmacokinetics of the ISL@ZLH NP-pow were examined in
plasma and organs, compared with those of aqueous ISL@ZLH NPs. Result: The ideal
particle size of the ISL@ZLH NP pow was 118 nm, which was not filtered out by the
glomerulus and allowed the drug to be delivered to the lesions more effectively. Cellular
uptake and biodistribution of the ISL@ZLH NP-pow in vivo and in vitro showed prolonged
storage in the organs. In addition, cryopreserved ISL@ZLH NP-treated tumors
showed significant anti-proliferative and anti-migratory effects through the downregulation
of the PI3K-Akt-mToR and MMP2/9 signaling pathways. Conclusion: These results
suggest that oral ingestion of cryopreserved ISL@ZLH NP has the potential for longterm
storage and can be employed as a clinical therapeutic approach to treat TNBC.
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DRUG DEVELOPMENT RESEARCH
·
2025
·Vol. 86
·期 1
·e70051
·
IF 4.2
Qiwen Shi,Tao Zhou,Wenjun Hou,Yuqi Zhou,Shufen Deng,Ying Song
Diabetes nephropathy (DN) is a severe diabetic chronic microvascular complication and the major cause of end-stage renal disease (ESRD). Our study aimed to investigate the effects of isoliquiritigenin (ISL) a natural flavonoid compound on DN and to explore the underlying mechanisms. The db/db mice were received intragastric treatments of ISL (5, 10, or 20 mg/kg), vehicle or positive drug metformin (300 mg/kg) once a day for 12 weeks, and the db/m mice treated with vehicle were used as controls. ISL significantly ameliorated pathological changes and functional injury in the kidneys of db/db mice in a dose-dependent manner. The administration of 20 mg/kg ISL reduced the levels of serum creatinine (Scr; 49.0 ± 1.7 vs. 56.9 ± 2.9 μmol/L; p < 0.01), blood urine nitrogen (BUN; 9.6 ± 1.3 vs. 12.0 ± 1.1 mmol/L; p < 0.05), albumin to creatinine ratio (ACR; 1925.8 ± 798.1 vs. 4269.4 ± 925.6 μg/mg; p < 0.01) and urinary albumin (276.2 ± 39.9 vs. 576.9 ± 108.9 μg; p < 0.05). Further study identified advanced glycation end product (AGE)–receptor for AGE (RAGE) axis as a target of ISL. ISL (20 mg/kg) lowered renal AGE level (2.5 ± 0.5 vs. 3.8 ± 0.6 μg/mg; p < 0.01) and RAGE expression, leading to improvements in renal fibrosis, oxidative stress, and inflammation. To sum up, our study demonstrated that ISL displayed preventive effects on the experimental model of DN through suppressing AGE–RAGE pathway, and provided some insights into the application of ISL in DN treatment.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Yi-Min Ren,Yu Chen,Chang-Mao Jiang,Xiong Chen,Hong-Jin Qin,Zhu Wei,Xue Rao,Yu-Chen Wang,Ning-Ze Jiang,Jin-Yuan Luo-Qian,Ying-Nan Song,Xiao-Hua Zou,Jiang Zheng,Hong-Jin Chen
Chronic inflammatory pain (CIP) poses a significant medical challenge, with current pharmacological treatments often associated with considerable side effects. The identification of effective therapeutic targets and the development of novel agents remain major hurdles. Exploring neuroimmune interactions and utilizing network pharmacology to uncover compounds capable of simultaneously modulating pain and inflammation presents a promising strategy. In this study, the therapeutic efficacy, potential targets, and underlying mechanisms of isoliquiritigenin (ISL) were investigated in a mouse model of CIP induced by complete Freund's adjuvant (CFA) paw pad injection. Single-dose ISL (20 or 60 mg/kg) attenuated CFA-induced hypersensitivity in an acute screening experiment, after which we investigated sustained efficacy using ISL (10 mg/kg) once daily for 7 days. ISL treatment significantly reduced paw swelling, mechanical allodynia, and thermal hyperalgesia. Additionally, ISL lowered the levels of IL-6, TNF-α, and VCAM-1 in both dorsal root ganglia (DRG) and skin tissues, along with a significant reduction in ERK phosphorylation. Network pharmacology analysis and molecular docking suggested CCR2 as a potential target of ISL. Further investigation revealed that ISL attenuated CCL7-induced CCR2 signaling activation. To validate the involvement of CCR2, siRNA-mediated knockdown of CCR2 was performed via DRG injection. This intervention suppressed ISL's analgesic and anti-inflammatory effects in CIP mice and CCL7 paw pad injection-induced pain and inflammation. Moreover, activation of ERK using tert-butylhydroquinone in CCR2 knockdown mice exacerbated CFA-induced inflammatory responses. These findings suggest that ISL alleviates CIP by targeting the CCL7/CCR2 axis and suppressing ERK-mediated inflammation.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2021
·
IF 4.932
Lu Wang,Xiaohui Wang,Lina Kong,Shuyuan Wang,Kai Huang,Jingjing Wu,Changyuan Wang,Huijun Sun,Kexin Liu,Qiang Meng
Acute liver failure (ALF) is a dramatic liver disease characterized by large areas of inflammation. However, there are no available effective targeted drugs for ALF treatment. In the study, serum biochemical index and H&E were used to explore the amelioration of the liver histopathological changes. The oxidative stress kits, quantitative real-time PCR, western blot, immunohistochemistry, immunofluorescence staining, reactive oxygen species (ROS), and siRNA were used to elucidate the mechanisms underlying isoliquiritigenin (ISL) protection. The results showed that ISL significantly improved the liver pathological changes. Furthermore, ISL reduced oxidative stress by altering the expression of PGC-1α, Nrf2, HO-1, NQO1, Keap1, GCLC, and GCLM in damaged hepatocytes. Moreover, the levels of inflammation-related genes including NLRP3 inflammasome, IL-1β, IL-6, TNF-α, iNOS, and Mip-2 were repressed by ISL. In addition, ISL alleviated LPS/D-GalN-induced hepatocytes apoptosis by increasing the Bcl-2/Bax ratio and suppressing the expression of cleaved caspase-3. Further in vivo and in vitro evidence proved the involvement of the PGC-1α/Nrf2 signaling pathway in ISL protection. In conclusion, ISL improves the ability of anti-oxidative stress, alleviates inflammatory reaction, apoptosis, and inhibits NLRP3 inflammasome to protect lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced ALF through activating the PGC-1α/Nrf2 pathway, which provides the possibility for the treatment of ALF.
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INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2017
·Vol. 40
·期 6
·1709-1718
·
IF 2.341
Baochao Ji,Wentao Guo,Hairong Ma,Boyong Xu,Wenbo Mu,Zhendong Zhang,Abdusami Amat,Li Cao
Isoliquiritigenin (ISL), a natural flavonoid extracted from licorice, has been demonstrated to exert attenuation of the nuclear factor-κB (NF-κB) signaling pathway and anti-inflammatory activity in a wide variety of cells. In the present study, the authors first evaluated the effects of ISL on cartilage degeneration in interleukin-1β (IL-1β)-stimulated chondrocyte-like ATDC5 cells and in a mouse model of osteoarthritis (OA). The data of a cell counting kit-8 and flow cytometry assay indicated that ISL suppressed the inhibitory effect of IL-1β on cell viability. The mRNA and protein expression levels of cyclooxygenase-2 and matrix metalloproteinase-13 were significantly decreased, while the expression of collagen II was increased, as indicated by RT-qPCR and western blot analysis following the chondrocyte-like ATDC5 cells were co-intervened with IL-1β and ISL for 48 h. Also, ISL attenuated protein expressions level of pro-apoptotic Bax, cleaved-caspase-3 and cleaved-caspase-9 and promoted expression of anti-apoptotic Bcl-2. Moreover, ISL inhibited NF-κB p65 phosphorylation induced by IL-1β. In addition, ISL also increased improved the thickness of hyaline cartilage and the production of proteoglycans in the cartilage matrix in a mouse OA model. These results indicated that ISL exerted anti-inflammatory and anti-apoptotic effects on IL-1β-stimulated chondrocyte-like ATDC5 cells, which may be associated with the downregulation of the NF-κB signaling pathway. In this way, the data supported the conclusion that ISL may be a novel potential preventive agent suitable for use in OA therapy.
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