BIOORGANIC CHEMISTRY
·
2024
·
IF 4.5
Linlin Han,Hongyan Tan,Jungjoon Lee,Peng Wang,Yuqing Zhao
Based on the significant biological activities and the remarkable physical and chemical properties of 1 H -1,2,3-triazole pharmacophore, we herein adopted the strategy of click chemistry to combine the triazole fragment and the unique scaffold of 25-OCH 3 -PPD ( AD-1 ) to design a series of potent compounds inducing apoptosis and DNA damage. The anti-proliferative effect was verified by MTT assay and colony formation assay. DNA double-stand breaks (DSBs) were obtained by observing the nuclear focus formation and the protein expression of γ-H2AX. Cell cycle arrest was evaluated by the cycle-related proteins such as CDK2, CDK4, CDK6, Cyclin D1 and P 21. Apoptosis was assessed by flow cytometry, mitochondrial membrane potential (MMP) detection and the expression of apoptosis-related proteins. Reactive oxygen species (ROS) generation was measured with 2′, 7′-dichlorofluorescein diacetate (DCFH-DA) staining. According to SAR analysis, the most potent compound 6a exhibited great inhibitory effect against A549 cells, which IC 50 value of 2.84 ± 0.68 μM. Furthermore, 6a remarkably induced DNA damage, cell cycle arrest and apoptosis in A549 cells. 6a treatment increased the levels of ROS. Network pharmacology and molecular docking predicted the potential signaling pathways and ligand-receptor interactions, and the results of western blotting showed that 6a inhibited the PI3K/Akt/Bcl-2 signaling pathway by decreasing PI3K and Bcl-2 and total level of Akt expression, while Bax and Cyt c were increasing in 6a -treated A549 cells. As mentioned above, 6a has a potent inhibitory effect in A549 cells through induction of DNA damage, apoptosis via ROS generation and modulation of PI3K/Akt/Bcl-2 signaling pathway.
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npj Regenerative Medicine
·
2022
·Vol. 7
·期 1
·1-15
·
IF 14.404
Wu Jianjun,Qin Zainen,Jiang Xianfang,Fang Depeng,Lu Zhenhui,Zheng Li,Zhao Jinmin
Excessive reactive oxygen species (ROS) are one of the leading mechanisms in the initiation and development of osteoarthritis (OA). However, conventional injection of ROS-responsive drug delivery systems (DDSs) such as nanoparticles and hydrogels usually cannot provide effective treatment due to rapid clearance and degradation or low bioavailability. In this study, a ROS-responsive nanofiber membrane named PLA/PEGDA-EDT@rGO-Fucoxanthin (PPGF) is fabricated by electrospinning, wherein PEGDA-EDT served as the ROS-responsive motif, reduced graphene oxide (rGO) as the drug carrier and fucoxanthin (Fx) as the antioxidative and anti-inflammatory agent. The results demonstrated that the PPGF nanofiber membrane exhibited sustained and long-term Fx release behavior (at least 66 days) in response to hydrogen peroxide (H 2 O 2 ) in vitro. With low cytotoxicity and smart ROS responsiveness, PPGF showed excellent anti-inflammatory and antioxidative effects on IL-1β-induced chondrocytes by potent ROS scavenging potential and upregulation of antioxidative enzymes. It also demonstrated the attenuation of OA progression with the reduced Osteoarthritis Research Society International (OARSI) score by 93.17% in 8 weeks. The smart ROS-responsive, biodegradable and biocompatible nanofiber membranes possess great potential for OA therapy under arthroscopy.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2022
·
IF 5.714
Liping Wang,Tiantian Ji,Ye Yuan,Haoyu Fu,Yang Wang,Shaobo Tian,Jia Hu,Lin Wang,Zheng Wang
The dramatically increasing incidence and prevalence of inflammatory bowel disease (IBD) are reportedly related to a Western diet, which is characterized by high sugar consumption. Dietary simple sugars aggravate IBD in animal models. However, the mechanisms underlying this effect remain unclear. Given that high-fructose corn syrup (HFCS) is a major added sugar in food and beverages, we focus on HFCS and investigated the effects of HFCS on a dextran sulfate sodium (DSS)-induced murine colitis model and in RAW264.7 macrophages. Our data demonstrate that short-term consumption of HFCS aggravates colitis and upregulates the proportion of macrophages in IBD mice but not in healthy mice. We find that HFCS promotes proinflammatory cytokine production through reactive oxygen species (ROS)-mediated nuclear factor-κB (NF-κB) signaling in RAW264.7 macrophages. Furthermore, N-acetylcysteine (NAC), an ROS scavenger, alleviates HFCS-aggravated colitis in mice and inhibits the ROS-mediated NF-κB signaling pathway in RAW264.7 macrophages. Our work unveils the important role of macrophages in HFCS-induced exacerbation of colitis and reveals the mechanism of how HFCS immunologically aggravates IBD.
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SOUTH AFRICAN JOURNAL OF BOTANY
·
2021
·
IF 2.315
Kiren Mustafa,Shaoxuan Yu,Wen Zhang,Hassan Mohamed,Tahira Naz,Haifang Xiao,Yingxin Liu,Yusuf Nazir,Abu Bakr Ahmad Fazili,Shaista Nosheen,Xueyuan Bai,Yuanda Song
Liver cancer is one of the most frequent causes of cancer-related deaths worldwide. The current study sought to screen, for the first time, a Ficus carica variety from the Shandong province of China against hepatocellular (HepG2) cells. Crude extracts of F. carica with various polarities were prepared and screened against HepG2 cells. The acetone extract of the leaf (FLA) exhibited significant antiproliferative effects against HepG2 cells (IC 50 = 0.179 mg/mL) while producing the least toxicity on normal human umbilical vein endothelial cells (HUVECs). Biochemical evidence of apoptosis was confirmed by staining with DAPI and AO/EB. FLA also exhibited moderate anti-colonization potential against the population of HepG2 cells. It selectively arrested the cell cycle of HepG2 cells at the S phase and exerted anticancer activity by significantly increasing the reactive oxygen species (1.59 fold) inside the cells, which subsequently resulted in loss of the mitochondrial membrane potential as revealed by JC-1 probe assay. FLA downregulated the expression of tumor-promoter Transcription Factor (TP53), anti-apoptotic proteins (Bcl-2), and cell cycle regulatory kinases (CDK1, 5, 9) with respect to untreated cells for 24 h, 48 h, and 72 h. High-performance liquid chromatography (HPLC) of FLA revealed the presence of gallic acid and quercetin as major antiproliferative compounds along with trace amounts of rutin, luteolin, apigenin, benzoic acid, and β-sitosterol. Notably, our study showed FLA operating via novel mechanisms involving reactive oxygen species (ROS) generation and CDKs involvement in HepG2 cells. Thus, it suggests that FLA may be a potential source of new drugs in the treatment of liver cancer.
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BIOMATERIALS
·
2025
·
IF 12.9
Fang Zhang,Bingbing Zhao,Keqiang Lu,Xueping Zeng,Zikun Wang,Wei Chen,Yunyun Zhou,Juanjuan Peng,Lingzhi Zhao
Oxidative stress and fibrosis are core drivers of post-myocardial infarction dysfunction. Conventional therapies predominantly address either acute oxidative damage or chronic fibrosis, lacking strategies that concurrently target the two interconnected processes. Here, a microenvironment-responsive nanomedicine delivering nitric oxide (NO) and curcumin specifically to the infarcted heart is presented (named C@Si-NM). Constructed from glutathione-sensitive cyclic nitrate-trimethylene carbonate-polyethylene glycol block copolymer micelles crosslinked with silica, the system releases both NO and the encapsulated curcumin upon encountering elevated glutathione levels at the infarction site. In cardiomyocytes, NO suppresses the opening of mitochondrial permeability transition pore, inhibiting the release of reactive oxygen species, while curcumin directly acts as an antioxidant. In fibroblasts, NO inhibits the TGF-β/Smad pathway and curcumin downregulates the production of TGF-β, jointly suppressing fibrosis. The combined nanomedicine C@Si-NM significantly improved cardiac function in a rat model of MI after four weeks of treatment, resulting in an ejection fraction of 74 %. This value approached the normal range of 81 % and was superior to the outcomes observed with NO monotherapy at 62 % or curcumin monotherapy at 63 %. This strategy effectively mitigates both oxidative damage and fibrosis, bridging the gap between acute and chronic therapeutic interventions of myocardial infarction.
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PARTICULATE SCIENCE AND TECHNOLOGY
·
2025
·
IF 1.5
Xingwang Sun,Haibin Wu
Ferroptosis, which relies on iron (Fe) ions for the production of reactive oxygen species (ROS), is an effective approach for treating liver cancer. Cells will activate several mechanisms, such as decreasing Fe absorption and sequestering surplus Fe in ferritin, to diminish intracellular Fe levels. This study presents a straightforward, one-pot approach for the fabrication of bovine serum albumin (BS)-stabilized MnFe2O4 (MnFe@BS NPs) intended for liver cancer treatment in ferroptosis therapy. Cabozantinib (CA) and paclitaxel (PA), which can promote ferritin breakdown and augment uptake by elevating transferrin receptor and binding protein IRP2 levels, were encapsulated in MnFe@BS NPs to improve the liver cancer cytotoxic properties. The fabricated MnFe@BS-CA/PA NPs substantially elevate cellular Fe concentration, hence augmenting ROS production within HepG2 cells. Thus, the bimetallic nanozyme demonstrated a synergistic effect of MnFe, CA, and PA, providing a foundation for improving ferroptosis therapy for liver cancer.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2026
·
IF 5.2
Jianan Zhang,Yangli He,Yundi Wu,Tian Xie,Wanmeng Fu,Xilong Wu,Lei Zhou,Min Zeng
Effective management of myocardial ischemia/reperfusion (I/R) injury remains a clinical challenge. Epigallocatechin gallate (EGCG), a natural antioxidant, exhibits therapeutic potential in I/R models; however, it is limited by poor bioavailability and inadequate targeted delivery. Therefore, using a synergistic therapeutic strategy, we designed a nanoplatform (PB@PEI@FPBA-EGCG NPs, referred to as PPFE NPs) to address these limitations. PPFE NPs integrate Prussian blue nanoparticles (PB NPs) with EGCG, harnessing the multi-enzyme–mimicking activities of PB NPs (SOD/CAT mimetic, •OH scavenging) together with the pharmacological properties of EGCG. Notably, in this nanoplatform, PB NPs and EGCG demonstrate excellent synergistic therapeutic effects, characterized by enhanced ROS-responsive drug release and injured cardiac tissue-selected delivery. In vitro and in vivo studies confirmed the efficacy of PPFE NPs in neutralizing ROS, restoring mitochondrial homeostasis, and inhibiting apoptosis following I/R injury. Mechanistically, cardioprotection was mediated through the regulation of DJ-1 (PARK7) and its downstream pathways—Nrf2/ARE antioxidant signaling and ASK1/p38/JNK apoptotic regulation. Importantly, this study is the first to utilize native PB NPs as an EGCG carrier, exploiting their ROS scavenging ability and boronate ester bonds to improve EGCG loading efficiency and targeted delivery. Furthermore, we innovatively found that the combination of EGCG and DJ-1 may represent a key mechanism underlying the protective effects of EGCG against myocardial ischemia/reperfusion injury (MIRI). This work pioneers a ROS-responsive Prussian blue (PB) nanoplatform with superior synergistic efficacy. The study establishes PPFE NPs as a biocompatible nano-platform for myocardial I/R injury and provides a translatable strategy to optimize the clinical application of EGCG.
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
·
IF 4.7
Wenying Fu,Ying Yan,Chongchong Shu,Chenxin Xu,Yinghua Chen,Yiqun Xia,Jundixia Chen,Yunzhi Chen,Ri Cui,Peng Zou,Daoyong Ni
6-Methoxydihydrosanguinarine is a natural alkaloid derived from medicinal plants that exhibits significant antitumor activity, making it a promising candidate for cancer therapy. However, the exact molecular mechanisms underlying its effects require further investigation. In this study, we investigated the cytotoxicity and underlying mechanisms of 6-Methoxydihydrosanguinarine in human non-small cell lung cancer (NSCLC) cells. Our findings reveal that reactive oxygen species (ROS) accumulation is the key driver of its antitumor activity. Mechanistically, 6-Methoxydihydrosanguinarine activates the JNK signaling pathway and induces endoplasmic reticulum (ER) stress, both of which can be reversed by the ROS scavenger N-acetylcysteine (NAC). Interestingly, 6-Methoxydihydrosanguinarine also activates autophagy, and inhibition of autophagy reverses the JNK and ER stress pathway activation induced by 6-Methoxydihydrosanguinarine. Notably, 6-Methoxydihydrosanguinarine synergistically enhances cisplatin-induced NSCLC cell death, and this synergistic effect is abolished by NAC, highlighting the critical role of ROS accumulation in their combined efficacy. This study systematically elucidates the molecular mechanisms of 6-Methoxydihydrosanguinarine against NSCLC, revealing that, in addition to the JNK and autophagy pathways, ER stress also mediates its antitumor effects. Moreover, our data establish a rationale for exploring 6-Methoxydihydrosanguinarine in NSCLC therapy and highlight its combination with cisplatin as a potentially effective strategy.
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Scientific Reports
·
2026
·
IF 4.9
Zhang Wei,Zhu Xinghao,Shao Mingliang,Han Qi,Shen Hao,Zhang Kun,Chen Rui,Qi Dongmei,Xu Lijun,Wu Zongyao
The progression of hepatocellular carcinoma (HCC) was highly dependent on pathological angiogenesis, with tumor-associated macrophages (TAMs) serving as key mediators regulating angiogenesis within the tumor microenvironment. The role of protein tyrosine phosphatase 2 (SHP2), a multi-signaling pathway regulator containing an SH2 domain, in TAM-mediated angiogenesis remained unclear. This study aimed to elucidate the molecular mechanism by which SHP2 regulates HCC angiogenesis through the ROS/Src pathway in TAMs under hypoxic conditions. We employed a comprehensive approach. THP-1 macrophage cells were transfected with SHP2 shRNA lentivirus and co-cultured with HCC cell line Huh-7 cells. The co-cultured cells were then subcutaneously transplanted into nude mice. Tumor size was assessed via HE staining in nude mouse tumor formation assays. We engineered luciferase-transfected Huh-7 cells to establish an orthotopic HCC implantation model and measured tumor area via in vivo fluorescence imaging. THP-1 cells were respectively cultured in media supplemented with antioxidants, pro-oxidants, and Src inhibitors, followed by transfection with SHP2 shRNA lentivirus and SHP2 mock lentivirus. These cells were then co-cultured with Huh-7 cells and Hep3B cells, respectively. The proportion of CD68-positive cells detected by immunofluorescence staining was used to ensure that the observed effects in the study were primarily derived from tumor-associated macrophages. Western blot analysis was employed to detect expression levels of SHP2, ROS/Src pathway-related proteins, tumor migration-related proteins, and angiogenesis-related proteins in the cells. Relative fluorescence intensity of intracellular ROS in THP-1 cells was visualized using the fluorescent probe DCFH-DA combined with fluorescence microscopy. Cell migration and invasion capabilities were assessed via wound healing assays and transwell assays. Immunofluorescence staining further validated SHP2 expression levels in THP-1 cells. Additionally, we examined the effects of SHP2 on HCC angiogenesis using tube formation assays, Western Blot analysis, HE staining, and immunohistochemical staining for CD31. The impact of SHP2 on HCC cell proliferation was investigated through colony formation assays and cell cycle analysis by flow cytometry. Following co-culture of SHP2 shRNA-infected THP-1 cells with Huh-7 cells, nude mouse tumor formation assays and in vivo fluorescence imaging revealed significantly reduced tumor volume and area. Following antioxidant supplementation in THP-1 cell culture medium, western blot analysis revealed markedly reduced expression levels of ROS/Src pathway-associated proteins, tumor migration proteins, and angiogenesis-related proteins. Fluorescent probe-based fluorescence microscopy demonstrated decreased relative fluorescence intensity of ROS within tumor cells. Furthermore, Western blot and immunofluorescence staining experiments jointly demonstrated that SHP2 in TAMs can regulate the ROS/Src pathway. Wound healing assays, transwell assays, and tube formation assays demonstrated that SHP2 in TAMs enhanced HCC cell migration, invasion, and angiogenesis capabilities. Furthermore, HE staining and immunohistochemical staining for CD31 indicated that inhibiting ROS/Src pathway suppressed HCC angiogenesis. Colony formation assay and flow cytometry analysis revealed that SHP2 in TAMs promotes HCC proliferation and cell cycle progression via the ROS/Src pathway. Under hypoxic conditions, tyrosine phosphatase SHP2 in TAMs regulates angiogenesis in HCC through the modulation of the ROS/Src pathway.
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Frontiers in Immunology
·
2026
·
IF 7
Jiquan Shen,Changjian Zhou,Xinggao Wang,Yuxuan Chen,Run Liu,Liang Hong,Weiping Ji,Bo Wang
BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by severe synovial inflammation, joint deformities, and progressive tissue destruction. Celastrol (Cel), a natural triterpenoid with anti-inflammatory and antioxidant activity, is a promising therapeutic candidate for RA; however, its application is limited by poor aqueous solubility, low bioavailability, and systemic toxicity.PurposeThis study aimed to develop folate-modified liposomes encapsulating Cel (FA-Cel-LPs) to improve its solubility, stability, and joint accumulation, and to evaluate their anti-inflammatory efficacy and associated molecular changes in LPS-activated RAW264.7 macrophages and collagen-induced arthritis (CIA) rats.MethodsFA-Cel-LPs were prepared by thin-film hydration followed by extrusion and characterized for particle size, morphology, polydispersity index (PDI), encapsulation efficiency (EE), and in vitro release behavior. In LPS-activated RAW264.7 cells, cellular uptake, intracellular ROS levels, NF-κB nuclear translocation, COX-2/iNOS expression, and cytokine secretion were evaluated. In CIA rats, therapeutic efficacy was assessed by paw swelling, arthritis scores, in vivo fluorescence imaging, MRI, histological analysis, and micro-CT-based bone parameters. Safety was evaluated using hemolysis, serum biochemical analysis, and organ histology.ResultsFA-Cel-LPs showed a mean particle size of 110.65 ± 1.24 nm, an EE of 84.67 ± 2.55%, a PDI of 0.230 ± 0.018, and a sustained release profile with pH-dependent differences in vitro. In RAW264.7 cells, folate-modified liposomes showed greater cellular uptake and were associated with reduced ROS levels, attenuated NF-κB activation, and decreased COX-2, iNOS, and pro-inflammatory cytokine expression, with low cytotoxicity. In CIA rats, in vivo imaging suggested greater accumulation of FA-Cel-LPs in inflamed joints. Compared with free Cel and Cel-LPs, FA-Cel-LPs more effectively reduced paw swelling and joint inflammation while attenuating bone erosion and preserving joint architecture. Serum ALT and AST levels in the FA-Cel-LPs group remained within physiological ranges and were significantly lower than those in the free Cel group. Organ histology showed no obvious treatment-related injury, suggesting acceptable preliminary safety.ConclusionFA-Cel-LPs improved the solubility, formulation stability, and apparent joint accumulation of Cel and enhanced its anti-inflammatory and bone-protective effects in experimental RA. These effects were associated with reduced ROS/NF-κB/COX-2-related inflammatory changes, suggesting FA-Cel-LPs may represent a promising liposomal strategy for RA.
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Pharmaceutics
·
2026
·Vol. 18
·期 9
·1115
·
IF 6.9
Qian Chen,Hui Yang,Meili Pei,Yanxia Sun,Yubei Li,Sen Yu,Xiaofeng Yang
Background:The fibrous tumor extracellular matrix (ECM), driven by cancer-associated fibroblasts (CAFs), forms a physical barrier against drugs and immune cells, yet direct CAF elimination risks promoting metastasis.Methods:In this study, we developed a locally injectable hydrogel based on synergistic dynamic covalent crosslinking (imine and boronate ester bonds), enabling instant gelation, shear thinning, and dual-pH/ROS-responsive degradation. Two types of drug-loaded nanoparticles (NPs), coated with homotypic cell membranes, were incorporated into this hydrogel. In the acidic, reactive oxygen species (ROS)-rich tumor microenvironment (TME), the system responsively releases the antifibrotic drug SIS3 to reprogram CAFs while simultaneously delivering doxorubicin (DOX) specifically to tumor cells. Biological effects were evaluated in vitro using cell cultures and in vivo in mouse models.Results:This dynamic hydrogel-based co-delivery system effectively reprograms CAFs, reduces tumor mechanical stress, breaks the fibrotic barrier, and promotes the deep infiltration of chemotherapeutics and immune cells, thereby enhancing the efficacy of chemotherapy.Conclusions:This injectable pH/ROS-responsive dynamic covalent hydrogel, loaded with CAF- and cancer cell-targeting NPs, remodels the TME, enhances drug and immune cell penetration, and offers a promising biomaterial-based strategy for cervical cancer treatment.
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Advanced Healthcare Materials
·
2026
·
IF 11
Fazhen Luo,Xupeng Zhang,Yufan Guo,Jinxia Mi,Yihong Zhang,Juan Yang,Guowen Li,Yan Xie
In this work, we engineered a novel core–shell nanoplatform (TG@GPH) based on glycyrrhizic acid (GL) for enhanced mitochondrial-targeted therapy against triple-negative breast cancer (TNBC). Specifically, the amphiphilic structure of GL enabled encapsulation of triphenylphosphine-glycyrrhetinic acid (TPP-GA or TG) with a high loading capacity (> 24%); whereas its ortho-hydroxy groups facilitated the anchoring of a polyethylenimine-phenylboronic acid (PEI-PBA) inner shell via borate ester bonds, followed by electrostatic coating of a hyaluronic acid outer shell. The TG@GPH micelles exhibited good physiological stability and efficient uptake by MDA-MB-231 cells; however, they dissociated under acidic and elevated ROS conditions due to acid-labile cleavage of boronate ester bonds and ROS-triggered oxidative breakage of carbon-boron bonds, thereby rapidly releasing the TG payload. Thereafter, TG selectively targeted mitochondria and stimulated the opening of the mitochondrial permeability transition pores, resulting in mitochondrial impairment characterized by ROS overproduction, membrane potential depletion, and energy supply blockade, culminating in tumor cell apoptosis. Accordingly, TG@GPH suppressed tumor growth in MDA-MB-231 xenograft mouse models with an inhibition rate of 79.70%. Overall, the developed TG@GPH micelles displayed considerable potential for TNBC treatment and provided a compelling paradigm for transforming natural compounds into intelligent building blocks for sophisticated drug delivery systems.
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