JOURNAL OF ETHNOPHARMACOLOGY
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2024
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IF 4.8
Guo-Dong Zhuang,Si-Min Deng,Meng-Di Chen,Chao-Fan Deng,Wen-Ting Gu,Shu-Mei Wang,Dan Tang
Ethnopharmacological relevance Cognitive dysfunction associated with diabetes, known as diabetic encephalopathy (DE), is a grave neurodegenerative condition triggered by diabetes, and persistent inflammation plays a vital role in its development. The renowned traditional Chinese medicine Huang-Lian-Jie-Du Decoction (HLJDD) is clinically proven to manage diabetes mellitus and Alzheimer's disease and is famous for its heat-clearing and detoxifying effects. However, the underlying mechanisms through which HLJDD affects DE remain to be elucidated. Aim of the study To explore the beneficial effects of HLJDD on improving cognitive dysfunction in DE mice. Study design and methods A diabetic mouse was established through a high-fat diet and subsequent administration of streptozotocin over five consecutive days. After the animals were confirmed to have diabetes, they were treated with HLJDD. After oral administration of HLJDD or metformin for 14 weeks, behavioral tests were used to assess their cognitive capacity. Biochemical analyses were then performed to detect levels of glucose metabolism, followed by histological analyses to assess pathological damage. Furthermore, AGEs/RAGE/NF-κB axis related proteins were detected by Western blot or immunofluorescence techniques. An advanced UPLC-Q-Orbitrap HRMS/MS analytical technique utilizing a chemical derivatization strategy was employed for comprehensive metabolic profiling of carbonyl compounds in the plasma of DE mice. Results Pharmacological assessment revealed that HLJDD effectively mitigated cognitive dysfunction, normalized glucose metabolic imbalances, and repaired neuronal damage in DE mice. It reduced neuroinflammation by attenuating carbonyl stress, deactivating astrocytes and microglia, and preserving dopaminergic neurons. Additionally, metabolomics analysis revealed 18 carbonyl compounds with marked disparities between DE and control mice, with 12 metabolites approaching normal levels post-HLJDD intervention. Further investigations showed that HLJDD regulated inflammation and pyroptosis through suppressing AGEs/RAGE/NF-κB pathways. Conclusion Our study indicated that HLJDD could ameliorate carbonyl stress via the regulation of carbonyl compound metabolism profiling, and inhibiting the AGEs/RAGE/NF-κB pathway, thereby alleviating inflammation and pyroptosis to exert beneficial effects on DE.
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JOURNAL OF NANOBIOTECHNOLOGY
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2025
·Vol. 23
·期 1
·795
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IF 12.6
Zhang Yuanfeng,Yang Enguang,Zhang Xinyu,Shi Yibo,Fan Guangrui,Wang Yuhan,Tian Junqiang,Wang Hanzhang,Dong Zhilong,Wang Yingru,Cheng Liang,Zhao Zhiwen,Zhang Yonghai,Wang Baodui,Wang Zhiping
Background Juglone, a natural naphthoquinone compound, exhibits potent anticancer activity but faces clinical limitations due to poor solubility, low bioavailability, and systemic toxicity. While tumor microenvironment-responsive drug activation strategies offer a promising solution, achieving precise spatial control over the conversion of non-toxic precursors into cytotoxic agents remains a significant challenge. Methods We developed DHN@Pt/PtMBCPsNSs, a platinum (Pt)-methylene blue (MB)- based nanoscale sonosensitizer, to enable ultrasound-triggered on-demand juglone synthesis within tumors. The system was evaluated in bladder cancer models including cell lines, patient-derived organoids (PDOs) and patient-derived tumor xenograft (PDX) models, assessing tumor uptake, intracellular distribution, hypoxia modulation (“H 2 O 2 -O 2 -¹O 2 ” cascade), oxidative stress markers (SOD, GSH, MDA, GSSG), and cell death pathways (apoptosis/pyroptosis). Transcriptome sequencing was performed to elucidate molecular mechanisms. Results DHN@Pt/PtMBCPsNSs were internalized by UMUC-3 and T24 cells and primarily accumulated within the mitochondrial compartments. The platinum-based components catalytically exhausted GSH via redox cycling. DHN@Pt/PtMBCPsNSs triggered the production of O 2 and ¹O 2 after local US irradiation, alleviating hypoxia and selectively converting dihydroxynaphthalene (DHN) to juglone in tumors, which reducing the systemic toxicity of juglone. The nanosystem further disrupted cellular redox balance by triggering depletion of antioxidant defenses (SOD and GSH) and reducing the ratio of GSH/GSSG. In vitro cell experiments and PDOs experiments demonstrated that DHN@Pt/PtMBCPsNSs combined with US irradiation can significantly inhibit bladder cancer cell proliferation, induce apoptosis, and regulate pyroptosis via the ROS-mediated caspase 3/GSDME signaling pathway. In the PDX model, DHN@Pt/PtMBCPsNSs accumulated at the tumor site and significantly inhibited tumor growth under US irradiation. Conclusions As a novel sonosensitizer and pyroptosis inducer, DHN@Pt/PtMBCPsNSs achieve a precise synergistic effect of chemotherapy and sonodynamic therapy within cells, while minimizing adverse effects on normal cells and overcoming the limitations associated with natural chemotherapeutic agents. This approach may advance clinical translation of natural anticancer agents. Graphical
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Journal of Integrative Agriculture
·
2023
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IF 4.8
Ke-da SHI,Yan LI,Min-sheng XU,Kun-li ZHANG,Hong-chao GOU,Shao-lun ZHAI,Chun-ling LI
Streptococcus suis serotype 2 ( S. suis 2) is a zoonotic pathogen that clinically causes severe swine and human infections (such as meningitis, endocarditis, and septicemia). In order to cause widespread diseases in different organs, S. suis 2 must colonize the host, break the blood barrier, and cause exaggerated inflammation. In the last few years, most studies have focused on a single virulence factor and its influences on the host. Membrane vesicles (MVs) can be actively secreted into the extracellular environment contributing to bacteria-host interactions. Gram-negative bacteria-derived outer membrane vesicles (OMVs) were recently shown to activate host caspase-11-mediated non-canonical inflammasome pathway via deliverance of OMV-bound lipopolysaccharide (LPS), causing host cell pyroptosis. However, little is known about the effect of the MVs from S. suis 2 (Gram-positive bacteria without LPS) on cell pyroptosis. Thus, we investigated the molecular mechanism by which S. suis 2 MVs participate in endothelial cell pyroptosis. In this study, we used proteomics, electron scanning microscopy, fluorescence microscope, western blotting, and bioassays, to investigate the MVs secreted by S. suis 2. First, we demonstrated that S. suis 2 secreted MVs with an average diameter of 72.04 nm, and 200 proteins in MVs were identified. Then, we showed that MVs were transported to cells via and dynamin-dependent endocytosis. The S. suis 2 MVs activated NLRP3/Caspase-1/GSDMD canonical inflammasome signaling pathway, resulting in cell pyroptosis, but it did not activate the caspase-4/-5 pathway. More importantly, endothelial cells produce large amounts of reactive oxygen species (ROS) and lost their mitochondrial membrane potential under induction by S. suis 2 MVs. The results in this study suggest for the first time that MVs from S. suis 2 were internalized by endothelial cells via mainly dynamin-dependent endocytosis and might promote NLRP3/caspase-1/GSDMD pathway by mitochondrial damage, which under induction produced mtDNA and ROS, leading to the pyroptosis of endothelial cells.
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2026
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IF 5.7
Pingting Wu,Weilai Chen,Jie Li,Jiayi Xing,Haote Wu,Jingyang Tong,Ping Chen,Haibin Tong,Yongping Chen,Chenwei Pan
Acetaminophen (APAP) overdose causes acute liver injury (ALI) by triggering regulated hepatocyte death. While Imperata cylindrica (Imperatae Rhizoma) (IR) is used in traditional medicine for its hepatoprotective effects, its active compounds and their capacity to modulate this pyroptotic switch remain unknown. In the present study, friedelin (FRI) and 6-methoxyflavone (6-METH) were identified as the principal active compounds of IR, and their protective effects against APAP-induced ALI were evaluated in vivo and in vitro. The results showed that both FRI and 6-METH significantly ameliorated APAP-induced liver injury and reduced hepatocyte death. Mechanistically, their hepatoprotective effects were associated with AKT1-dependent activation of the PI3K/AKT pathway, accompanied by suppression of Caspase-3/ Gasdermin E (GSDME) signaling and attenuation of apoptosis and pyroptosis. Moreover, pharmacological inhibition or genetic silencing of AKT1 markedly weakened these protective effects. Taken together, these findings suggest that FRI and 6-METH are major hepatoprotective constituents of IR and that modulation of the AKT1-mediated Caspase-3/GSDME pathway may contribute to their protective actions against APAP-induced ALI. These findings validate its active compounds as promising therapeutic leads for ALI.
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CELL BIOLOGY AND TOXICOLOGY
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2026
·Vol. 42
·期 1
·68
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IF 5.7
Li Ting,Feng Mengxiao,Wang Ping,Jiang Miao,Cui Jaiyu,Jin Mengxia,Song Congying,Lin Liying,Lu Yuan-Qiang
Baicalein, a naturally occurring flavonoid with well-documented anti-inflammatory and neuroprotective effects, has shown therapeutic promise in multiple models of neurological disorders. However, whether baicalein can counteract diquat-induced neurotoxicity remains uncertain. This study reveals that baicalein alleviates diquat-induced neuroinflammation and microglial pyroptosis in mice in a gut microbiota (GM)-dependent manner. In the in vivo experiments, multi-omics analyses demonstrated that baicalein elevates the GM-derived metabolite indole-3-propionic acid (IPA), which was sufficient to suppress pyroptosis. In parallel, IPA was identified as a critical mediator of baicalein's neuroprotective effects, as exogenous IPA administration recapitulated baicalein's protection, and baicalein treatment significantly elevated IPA levels. Mechanistically, through inhibiting the DEAD-box helicase 3 X-linked / GTPase-activating protein (SH3 domain) binding protein 1 pathway by in vitro experiments. Our study demonstrated that baicalein mitigates diquat-induced neuroinflammation, underscoring the therapeutic potential of targeting the GM to counteract herbicide-related neurotoxicity. Graphical
The alternative text for this image may have been generated using AI.
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BRITISH JOURNAL OF CANCER
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2022
·Vol. 128
·期 2
·219-231
·
IF 9.075
Yang Bingxue,Xie Xinran,Lv Dazhao,Hu Jiajun,Chen Yuyun,Wu Zhaoyu,Luo Shuyue,Zhang Shiyi
Background Hand-foot syndrome (HFS) is a serious dose-limiting cutaneous toxicity of capecitabine-containing chemotherapy, leading to a deteriorated quality of life and negative impacts on chemotherapy treatment. The symptoms of HFS have been widely reported, but the precise molecular and cellular mechanisms remain unknown. The metabolic enzyme of capecitabine, thymidine phosphorylase (TP) may be related to HFS. Here, we investigated whether TP contributes to the HFS and the molecular basis of cellular toxicity of capecitabine. Methods TP-/- mice were generated to assess the relevance of TP and HFS. Cellular toxicity and signalling mechanisms were assessed by in vitro and in vivo experiments. Results TP-/- significantly reduced capecitabine-induced HFS, indicating that the activity of TP plays a critical role in the development of HFS. Further investigations into the cellular mechanisms revealed that the cytotoxicity of the active metabolite of capecitabine, 5-DFUR, was attributed to the cleavage of GSDME-mediated pyroptosis. Finally, we demonstrated that capecitabine-induced HFS could be reversed by local application of the TP inhibitor tipiracil. Conclusion Our findings reveal that the presence of elevated TP expression in the palm and sole aggravates local cell cytotoxicity, further explaining the molecular basis underlying 5-DFUR-induced cellular toxicity and providing a promising approach to the therapeutic management of HFS.
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Diabetology & Metabolic Syndrome
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2023
·Vol. 15
·期 1
·1-13
·
IF 4.8
Li Tianrong,Yang Jingjing,Tan Anjun,Chen Hewen
Background Irisin plays a key role in metabolic diseases, including type 2 diabetes mellitus (T2DM). However, the mechanism underlying the link between irisin and the development of T2DM, particularly in pancreatic islet β-cells, remains unknown.Methods In vitro, Min6 cells were treated with high glucose (HG) to generate T2DM cell models. GSDMD-N staining, Western blotting assays, and ELISA were performed to measure the expression levels of GSDMD, caspase 1, IL-1β, and IL-18. Next, the NLRP3 stimulator, ATP, was used to assess the effect of irisin on NLRP3 inflammasome. To evaluate the function of the Nrf2-TrX/TXNIP signaling axis, the Nrf2 inhibitor ML385 was used. For in vivo assessment, we first established T2DM model mice. Then, hematoxylin and eosin (H&E) staining was performed to observe the islet morphology, and the immunofluorescence technique was used to examine the mass of α and β cells. To confirm the role of the Nrf2-TrX/TXNIP signaling axis, ML385 was injected into the mice. Immunofluorescence of Nrf2, caspase 1, and GSDMD was detected in the islet cells of the model mice to verify the results.Results We found that irisin treatment significantly decreased the expression of GSDMD-N (P31) and cleaved caspase-1 (p20), decreased caspase1 activity, and inhibited the secretion of IL-1β and IL-18 in HG-treated Min6 cells. We also found that irisin inhibited oxidative stress and NLRP3 expression by activating the Nrf2-TrX/TXNIP signaling axis. Additionally, in the T2DM model mice, irisin enhanced the function of islet cells, decreased insulin resistance, and preserved the morphology of pancreatic islets.Conclusion We showed in this study that irisin can be used for treating pyroptosis in HG-induced islet β-cells and T2DM model mice. We also found that irisin inhibits pyroptosis and oxidative stress by inhibiting the NLRP3-GSDMD pathway and activating the Nrf2-TrX/TXNIP signaling axis.
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International Journal of Nanomedicine
·
2023
·
IF 8
Qi Lou,Lu Pan,Shengjin Xiang,Yueting Li,Jiahui Jin,Jingyang Tan,Baoshan Huang,Kaihui Nan,Sen Lin
Introduction Benzalkonium chloride (BAC) is widely employed as a preservative in eye drops, which will cause the death of corneal epithelial cells due to ROS production, DNA strand breakage, and mitochondrial dysfunction, resulting in dry eye disease (DED)-like changes in ocular surface tissues. In this study, Melatonin (MT) liposomes (TAT-MT-LIPs) designed by loading MT into TAT-modified liposomes have been developed, characterized, and used for inhibiting BAC-induced DED (BAC-DED).Methods The TAT was chemically grafted onto the Mal-PEG2000-DSPE by Michael’s addition between the sulfhydryl group in TAT and the maleimide group in Mal-PEG2000-DSPE. TAT-MT-LIPs were prepared using film dispersion followed by the extrusion method and topically treated in rats once a day. BAC-DED was induced in rats by topical administration with 0.2% BAC twice daily. Defects, edema, and inflammation of the corneas, as well as IOP, were examined. Histologic analyses of corneas were performed to assess the change of mitochondrial DNA oxidation and NLRP3/Caspase-1/GSDMD signaling transduction.Results After topical administration, TAT-MT-LIPs significantly alleviated DED-clinical symptoms of experimental animals by inhibiting tissue inflammation and preventing the loss of the corneal epithelium and conjunctival goblet cells. Our data suggested continuous ocular surface exposure of BAC-induced NLRP3/Caspase-1/GSDMD mediated corneal epithelium pyroptosis, which was not reported before. BAC caused substantial mt-DNA oxidation, which promoted the transduction of NLRP3/Caspase-1/GSDMD and consequent corneal epithelium pyroptosis. TAT-MT-LIPs could efficiently suppress the BAC-induced corneal epithelium pyroptosis and inflammation by inhibiting mt-DNA oxidation and the subsequent signal transmission.Conclusion NLRP3/Caspase-1/GSDMD mediated corneal epithelium pyroptosis is involved in the development of BAC-DED. The present study provided new insights into the adverse effects of BAC, which can serve as a new target for protecting corneal epithelium when applying BAC as a preservative in eye drops. The developed TAT-MT-LIPs can efficiently inhibit BAC-DED and give great potential to be developed as a new DED treatment.
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CURRENT PHARMACEUTICAL DESIGN
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2023
·
IF 3.1
Yi Shi,Qian Wu,Yi Lu,Ling-Peng Meng,Xiao-Ling Xu,Xiao-Juan Wang,Wei Chen
Aim We aimed to design RGD-anchored liposomes encapsulating an antipyroptosis drug that could efficiently target macrophages and relieve the rate of cytokine release syndrome, providing a new strategy for sepsis treatment, especially sepsis-induced acute renal injury. Background Sepsis is a clinical syndrome of life-threatening organ dysfunction caused by host response disorders due to infection. Sepsis has a high incidence and remains one of the leading causes of death worldwide. Objective Macrophage-mediated pyroptosis plays an important role in the occurrence and development of cytokine release syndrome and organ injury caused by sepsis. Curcumin can inhibit inflammasome assembly and slow the progression of pyroptosis by scavenging intracellular reactive oxygen species, but it has poor water solubility and low bioavailability. The emergence of drug-delivery nanosystems has overcome this problem, but there is still a lack of research on how to accurately deliver antipyroptotic drugs to innate immune cells and subsequently hinder pyroptosis. Methods We constructed a curcumin-loaded RGD-modified liposome (RGD-lipo/Cur) and demonstrated that RGD-lipo/Cur could effectively target macrophages. Results In vitro , RGD-lipo/Cur reduced the upregulation of caspase-1, caspase-3, NLRP3, IL-1β and GSDMD, inhibiting pyroptosis, reducing oxidative stress, and attenuating the proinflammatory cytokine cascade. Conclusion RGD-lipo/Cur was considered to have great potential for sepsis treatment.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
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IF 5.6
Na Li,Fanghan He,Yunxiao Shang
Obese asthma is a form of refractory asthma with inflammation as the underlying mechanism. The specific mechanism of action of anti-inflammatory growth differentiation factor 15 (GDF15) in obese asthma is unclear. The purpose of this study was to explore the effect of GDF15 on cell pyroptosis in obese asthma and to determine its mechanism of airway protection. Male C57BL6/J mice were fed with a high-fat diet, sensitized, and challenged with ovalbumin. Recombinant human (rh)GDF15 was administered 1 h before the challenge. GDF15 treatment significantly reduced airway inflammatory cell infiltration, mucus hypersecretion and airway resistant, and decreased cell counts and inflammatory factors in bronchoalveolar lavage fluid. Serum inflammatory factors decreased, and the increased levels of NLR family pyrin domain containing 3 (NLRP3), caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and gasdermin-D (GSDMD-N) in obese asthmatic mice were inhibited. Furthermore, the suppressed phosphoinositide 3-kinase (PI3K)/AKT signal pathway was activated after rhGDF15 treatment. The same result was obtained by overexpression of GDF15 in human bronchial epithelial cells induced by lipopolysaccharide (LPS) in vitro, and the effect of GDF15 was reversed after the application of a PI3K pathway inhibitor. Thus, GDF15 could protect the airway by inhibiting cell pyroptosis in obese asthmatic mice through the PI3K/AKT signaling pathway.
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2024
·
IF 4.2
Yiming Sun,Hui Cai,Daofeng Yang,Nengyi Yu,Lejie Sun,Jingxuan Xu,Hongwei Yuan,Rong Yang,Lele Song,Hao Liu,Chengyao Ma,Zhe Liu
β-arrestin2 is a versatile protein for signaling transduction in brain physiology and pathology. Herein, we investigated the involvement of β-arrestin2 in pharmacological effects of fluoxetine for depression. A chronic mild stress (CMS) model was established using wild-type (WT) and β-arrestin2 −/− mice. Behavioral results demonstrated that CMS mice showed increased immobility time in the tail suspension test and forced swimming test, elevated concentrations of pro-inflammatory factors in peripheral blood, increased expression of pyroptosis-related proteins, and increased co-labeling of glial fibrillary acidic protein and Caspase1 p10 in the hippocampus compared to the CON group. Treatment with fluoxetine (FLX) ameliorated these conditions. However, compared with the β-arrestin2 −/− CMS group, these results of the β-arrestin2 −/− CMS + FLX group showed no significant changes. These results suggested that the above effects of FLX could be eliminated by knocking out β-arrestin2. Mass spectrometry implying that FLX promoted the binding of β-arrestin2 to the NLRP2 inflammasome of depressed mice. Subsequently, the results of the cellular experiments suggested that the 5HT 2B receptor antagonist may attenuate L-kynurenine + ATP-induced cell pyroptosis by attenuating NLRP2 binding to β-arrestin2. We further found that the lack of β-arrestin2 eliminated the anti-pyroptosis effect of fluoxetine. In conclusion, β-arrestin2 is an essential protein for fluoxetine to alleviate pyroptosis in the hippocampal astrocytes of CMS mice. Mechanistically, we found that the 5-HT 2B R-β-arrestin2-NLRP2 axis is vital for maintaining the antidepressant effects of fluoxetine.
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Journal of Inflammation Research
·
2025
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IF 4.1
Bingyan Gu,Yuying Chen,Huifang Xu,Kunyu Zhan,Keying Zhu,Huan Luo,Yanqun Huang,Hanbing Zeng,Wenbiao Zheng,Kun Tian,Hongfeng Ruan
Purpose Chlorpyrifos (CPF), a widely used organophosphate pesticide in agriculture, particularly in China, has raised significant environmental and health concerns due to its persistence and bioaccumulation. While CPF-induced toxicity in multiple organ systems has been documented, its long-term impact on thyroid homeostasis and the underlying mechanisms remain poorly understood. This study aimed to investigate the subchronic effects of CPF on thyroid function and elucidate the underlying mechanisms of CPF-induced thyroid toxicity.Methods The study utilized 4-week-old male C57BL/6J mice as experimental subjects. These mice were exposed to CPF via intragastric gavage at doses of 3 or 6 mg/kg for a duration of 8 weeks. Throughout the study period, various parameters were assessed, including body weight, serum antioxidant capacity, thyroid endocrine function and structure, apoptosis markers, inflammatory cytokines, and relevant molecular pathways.Results The study revealed that CPF exposure resulted in significant systemic toxicity, manifested through reduced body weight and impaired serum antioxidant capacity. Examination of thyroid-specific effects showed disrupted thyroid endocrine function and structure, accompanied by increased apoptosis and elevated inflammatory cytokines. At the molecular level, CPF significantly stimulated thyroid follicle cell pyroptosis by upregulating the expression of Nlrp3, Caspase-1, and Gsdmd. Further mechanistic analysis demonstrated that CPF activated thyroid follicular cell pyroptosis by modulating the Nrf2/Keap1 antioxidative pathway and enhancing phosphorylation of p65 via NF-κB signaling.Conclusion This comprehensive investigation provides novel insights into the mechanisms of CPF-induced thyroid toxicity. The findings demonstrate that CPF exposure compromises thyroid homeostasis through the induction of follicular cell pyroptosis and modulation of the Nrf2/Keap1/NF-κB signaling axis, highlighting the potential health risks associated with CPF exposure and its impact on thyroid function.
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