Escin Ia ameliorates DSS-induced chronic colitis in mice by inhibiting inflammation and oxidative stress via the LOXL2/MMP-9 pathwayYan, Xu, Zhu
et alJ Ethnopharmacol (2025) 345, 119623
Abstract: Aesculus wilsonii Rehd.'s dried mature seeds are the source of escin, a significant triterpenoid saponin. Aesculus wilsonii Rehd was first mentioned in the Compendium of Materia Medica, according to the Chinese Pharmacopoeia. It possesses the effectiveness of anti-inflammatory as well as treating gastrointestinal disorders. Escin Ia is the primary active component of escin, exhibiting significant antioxidant and anti-inflammatory properties. An increasing number of studies have demonstrated that escin exhibits a broad spectrum of pharmacological activities beneficial for the protection against gastrointestinal diseases.Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) that can be managed through pharmacological treatment; however, it features a high recurrence rate as well as propensity for complications. Therefore, reducing the rate of recurrence and improving the recurrence symptoms should be the primary focus of clinical prevention and treatment. Therefore, this research aims to study the effects of escin Ia on inflammation as well as oxidative stress in mice with chronic UC and to explain the molecular mechanisms underlying its potential to improve recurrent symptoms in UC mice.A mouse model of colitis produced via dextran sodium sulfate (DSS) was developed for in vivo studies. A model of inflammation was created in vitro using caco-2 cells that were generated by lipopolysaccharide (LPS). Through the observation of colitis symptoms and histological morphology in mice, the protective effect of escin Ia against colitis was ascertained. The enzyme-linked immunosorbent assay (ELISA) and biochemical kits were then harnessed to measure the levels of oxidative stress markers as well as inflammatory factors. Additionally, to identify the possible target and molecular mechanism of escin Ia, qRT-PCR and western blotting, immunofluorescence, molecular docking, and molecular dynamics modeling were employed.We demonstrated that escin Ia remarkably improved the colitis symptoms as well as histological features of DSS-treated mice, lowered the levels of proinflammatory cytokines as well as oxidative stress biomarkers, and subsequently restored the permeability of the intestinal mucosa. Additionally, high expression of LOXL2 significantly reduced the protective effects of escin Ia in both inflamed mice and Caco-2 cells. Furthermore, escin Ia exhibited a strong binding affinity and notable stability with LOXL2.Escin Ia inhibits inflammation and oxidative stress through the LOXL2/MMP-9 pathway, thereby restoring intestinal mucosal barrier function. Improved recurrent symptoms in mice with enteritis.Copyright © 2025 Elsevier B.V. All rights reserved.
Novel RORγt inverse agonists limit IL-17-mediated liver inflammation and fibrosisDabbaghizadeh, Dion, Maali
et alJ Immunol (2025)
Abstract: Liver fibrosis is a global health problem. IL-17A has proven profibrogenic properties in liver disease making it an interesting therapeutic target. IL-17A is regulated by RORγt and produced by Th17 CD4+ and γδ-T cells. We hypothesized that blocking IL-17A production will limit fibrosis progression by reducing recruitment of inflammatory cells. Herein, we tested the therapeutic potential of 2 novel RORγt inverse agonists (2,3 derivatives of 4,5,6,7-tetrahydro-benzothiophene) in a mouse model of CCl4-induced liver injury. C57BL/6 mice received 2 weekly injections of CCl4 for 4 weeks. As of week 3, mice were treated with the 2 novel inverse agonists (TF-S10 and TF-S14) and GSK805 as a positive control. Mice treated with the inverse agonists showed reduced immune cells infiltrate around the portal and central veins. TF-S14 significantly reduced AST levels (P < 0.05), and all inhibitors led to an improvement in relative liver weight (liver index). Flow cytometry analysis demonstrated that all inhibitors reduced the numbers of intrahepatic lymphocytes (CD4+, CD8+, and γδ-T cells, P < 0.05), and myeloid (CD11b+) cells (P = 0.04), most significantly eosinophils (P < 0.05). Furthermore, IL-17A production by CD4+ and γδ-T cells was diminished (P < 0.05 and P < 0. 01, respectively). Finally, livers from inhibitors-treated mice showed decreased markers of hepatic stellate cell activation (desmin and ɑ-smooth muscle actin [ɑ-SMA]) and significantly reduced expression of the profibrogenic genes (Col1a1, Acta, Loxl2, and Tgfβ) (P < 0.001). This was accompanied by diminished collagen deposition as measured by Picrosirius Red staining (P < 0.001). In conclusion, our results suggest that inhibition of the IL-17A pathway could be a promising therapeutic strategy for liver fibrosis.© The Author(s) 2025. Published by Oxford University Press on behalf of The American Association of Immunologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.
Acidity-unlocked glucose oxidase as drug vector to boost intratumor copper homeostatic imbalance-enhanced cuproptosis for metastasis inhibition and anti-tumor immunityWang, Xie, Zhu
et alBiomaterials (2025) 319, 123207
Abstract: As one of the key tools of biocatalysis, natural enzymes have received extensive attention due to their unique activity. However, the non-selective catalysis and early leakage induced by delivery dependency of natural enzymes can cause side effects on normal tissues. Moreover, although cuproptosis is an emerging tumor-inhibiting programmed cell death, the occurrence of cuproptosis leads to high expression of Cu-dependent lysyl oxidase-like 2 (LOXL2), which promotes tumor metastasis. Herein, in order to intelligently regulate the "OFF-to-ON" catalytic activity of glucose oxidase (a natural enzyme called GOx) and simultaneously inhibit tumor metastasis caused by Cu imbalance, an acidity-unlocked GOx system drug carrier was constructed by co-assembling Cu ions and omeprazole (OPZ) on GOx exposing sulfhydryl and hydrophobic pockets. The GOx activity is significantly inhibited due to the coordination of Cu ions with sulfhydryl groups and the interaction of hydrophobic small molecule OPZ with hydrophobic bags, which results in specificity for tumor cells and ensures the safety of GOx in blood circulation. Meanwhile, dysregulation of intracellular Cu homeostasis that impairs the Cu-dependence of LOXL2 not only inhibits critical signaling during epithelial-mesenchymal transformation (EMT) and extracellular matrix (ECM) remodelling to prevent tumor metastasis, but also exacerbates enhanced cuproptosis induced by tumor metabolic stress, thereby reversing the immunosuppressive microenvironment. This strategy of acidity-unlocked the catalytic function of natural enzymes and LOXL2 activity inhibition provides a novel option for enhancing cuproptosis to inhibit tumor metastasis and anti-tumor immunity.Copyright © 2025 Elsevier Ltd. All rights reserved.
Yiqi Juanshen decoction alleviates renal interstitial fibrosis by targeting the LOXL2/PI3K/AKT pathway to suppress EMT and inflammationTan, Deng, Liu
et alSci Rep (2025) 15 (1), 4248
Abstract: Chronic kidney disease (CKD) is a major health concern, with renal interstitial fibrosis (RIF) as a key feature. Effective management of RIF is crucial for treating CKD. Yiqi Juanshen decoction (YQJSD), as traditional Chinese medicine, has shown promising results in CKD treatment. This study evaluates YQJSD's effectiveness in ameliorating RIF and explores the underlying molecular mechanisms using the unilateral ureteral obstruction (UUO) model. YQJSD has been shown to effectively reduce serum creatinine and blood urea nitrogen levels, decrease extracellular matrix deposition, and down-regulate the expression of α-SMA, COL4α1, Fibronectin (FN). Mechanistically, YQJSD exerts its effects by modulating multiple pathways: it inhibits the NF-κB signaling pathway, inhibiting the expression of pro-inflammatory cytokines like NF-κB1, IL-1β, TNF-α, and CCR1. Simultaneously, YQJSD suppresses the epithelial-mesenchymal transition (EMT) by downregulating the expression of Snail1, Vimentin, Twist1, and FSP1, while increasing E-cadherin expression. Moreover, YQJSD can regulate the PI3K/AKT signaling pathway by decreasing the expression of LOXL2 and PIK3R1, along with p-AKT1/2/3. This modulation of the LOXL2/PI3K/AKT pathway contributes to the inhibition of both EMT and inflammation, highlighting a critical role in the therapeutic intervention against RIF. These findings suggest that YQJSD may serve as a promising therapeutic management of RIF in CKD patients.© 2025. The Author(s).
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