Science Advances
·
2024
·Vol. 10
·期 2
·
IF 11.7
Xuefeng Zhang,Xuyang Huang,Diancheng Hang,Jiaqi Jin,Shanshan Li,Yufu Zhu,Hongmei Liu
Posttraumatic neuroinflammation is a key driver of secondary injury after traumatic brain injury (TBI). Pyroptosis, a proinflammatory form of programmed cell death, considerably activates strong neuroinflammation and amplifies the inflammatory response by releasing inflammatory contents. Therefore, treatments targeting pyroptosis may have beneficial effects on the treatment of secondary brain damage after TBI. Here, a cysteine-alanine-glutamine-lysine peptide–modified β-lactoglobulin (β-LG) nanoparticle was constructed to deliver disulfiram (DSF), C-β-LG/DSF, to inhibit pyroptosis and decrease neuroinflammation, thereby preventing TBI-induced secondary injury. In the post-TBI mice model, C-β-LG/DSF selectively targets the injured brain, increases DSF accumulation, and extends the time of the systemic circulation of DSF. C-β-LG/DSF can alleviate brain edema and inflammatory response, inhibit secondary brain injury, promote learning, and improve memory recovery in mice after trauma. Therefore, this study likely provided a potential approach for reducing the secondary spread of TBI.
研究领域:
神经科学
·
药理学
·
纳米技术
·
炎症生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2024
·
IF 27.4
Kaiqiang Sun,Chen Yan,Xinyue Dai,Yangyang Shi,Fudong Li,Liang Chen,Jingchuan Sun,Yu Chen,Jiangang Shi
Low back pain resulting from intervertebral disc degeneration (IVDD) is a prevalent global concern; however, its underlying mechanism remains elusive. Single-cell sequencing analyses revealed the critical involvement of pyroptosis in IVDD. Considering the involvement of reactive oxygen species (ROS) as the primary instigator of pyroptosis and the lack of an efficient intervention approach, this study developed carbonized Mn-containing nanodots (MCDs) as ROS-scavenging catalytic biomaterials to suppress pyroptosis of nucleus pulposus (NP) cells to efficiently alleviate IVDD. Catalytic MCDs have superior efficacy in scavenging intracellular ROS and rescuing homeostasis in the NP microenvironment compared with N-acetylcysteine, a classical antioxidant. The data validates that pyroptosis plays a vital role in mediating the protective effects of catalytic MCDs against oxidative stress. Systematic in vivo assessments substantiate the effectiveness of MCDs in rescuing a puncture-induced IVDD rat model, further demonstrating their ability to suppress pyroptosis. This study highlights the potential of antioxidant catalytic nanomedicine as a pyroptosis inhibitor and mechanistically unveils an efficient strategy for the treatment of IVDD.
研究领域:
生物医学工程
·
纳米技术
·
骨科
·
细胞生物学
·
材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Animal Science and Biotechnology
·
2024
·Vol. 15
·期 1
·1-11
·
IF 6.3
Luo Junqiu,Wu Xiu,Chen Daiwen,Yu Bing,He Jun
Background Oxidative stress significantly impacts growth performance and liver function in piglets. Ferulic acid (FA) works as an antioxidant, however, the role and mechanism of FA in the regulation of diquat-induced oxidative stress in piglets are less known. This study was designed to investigate the effects of FA on growth performance and antioxidant capacity in piglets with diquat challenge. Methods Thirty-two healthy DLY (Duroc × Landrace × Yorkshire) piglets (13.24 ± 0.19 kg) were randomly divided into one of two diets including 0 or 4 g/kg FA for 14 d. On d 15, all pigs were intraperitoneally injected diquat or sterile saline. Results Dietary supplementation with ferulic acid (FA) significantly improved the average daily gain (ADG) and decreased feed-gain ratio (F/G) of piglets. Here, dietary FA supplementation reduced serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) activities in diquat challenged piglets. Furthermore, diquat infusion increased reactive oxygen radicals (ROS) level in liver, decreased the activities of total superoxide dismutase (T-SOD) and glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC) and increased malondialdehyde (MDA) content in the liver and serum. Supplementation with FA significantly increased T-AOC and T-SOD activities and decreased MDA and ROS levels. FA down-regulated gene and protein expression of Keap1, and up-regulated protein expression of Nrf2 and HO-1 in the liver of piglets with diquat challenge. Importantly, diquat challenge increased the ratio of late apoptosis, increased serum levels of IL-1β, IL-18 and lactate dehydrogenase (LDH), and up-regulated pyroptosis-related genes in the liver. FA supplementation reduced the ratio of late apoptosis and down-regulated mRNA expression of Caspase-1 . Accordingly, FA addition reduced concentration of IL-1β, IL-18, and LDH under diquat challenge. Conclusions Diquat-induced oxidative stress reduced growth performance and impaired liver function in piglets. Dietary FA supplementation enhanced the antioxidant capacity and reduced the degree of hepatocyte pyroptosis, thereby alleviating the oxidative damage in the liver and mitigating the impact of diquat on growth performance of piglets.
研究领域:
动物科学
·
营养学
·
毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Shuo Zhang,Shuang Guo,Pengyu Wang,Yan Song,Leiming Yang,Qiyu Sun,Qi Huang,Youzhi Zhang
Background Skeletal muscle atrophy is a clinical concern in diabetic nephropathy, and without effective therapeutic approaches. Massive evidence has demonstrated that dapagliflozin, a sodium-glucose co-transporter 2 inhibitor can relieve diabetic nephropathy by inhibiting glucose re-absorption or podocyte pyroptosis. Nevertheless, whether dapagliflozin could treat skeletal muscle atrophy or the potential protection mechanism in diabetic nephropathy mice is unclear. Methods The variety of approaches were used to assess the particular histology-associated characteristics, mRNA, and protein expression. These included examing the morphology of renal and skeletal muscle tissues through H&E staining, detecting mRNA and protein expression through real-time PCR and Western blot analysis, and monitoring fasting blood glucose levels by using Blood Glucose Monitor Test Kits. Results Dapagliflozin mitigated renal tissue injury with podocyte protein-nephrin and skeletal muscle atrophy effectively with mitochondrial-related proteins. Meanwhile, our research revealed that Casp3 was the target gene and dapagliflozin could decrease the expressions. Subsequently, we verified that dapagliflozin can effectively decrease canonical pyroptosis pathway proteins, which include Gasdermin D, NLRP3, Casp1, and ASC. Meanwhile, Palmitic acid (PA) induced Gasdermin E-N fragment (non-canonical pyroptosis protein) in C2C12 cells, and then released the inflammatory molecules such as IL-1β, IL-18, and NF-kappaB, which were suppressed by dapagliflozin treatment. Aside from that, dapagliflozin demonstrated a good binding affinity to the Casp3 and Gasdermin D protein, whereas it had a less binding affinity with NLRP3, Casp1, ASC, and Gasdermin E. At last, the Gasdermin D inhibitor can reverse the therapeutic effect of dapagliflozin. Conclusion Dapagliflozin alleviates skeletal muscle atrophy in diabetic nephropathy mice, which is through the Gasdermin D-mediated canonical pyroptosis pathway.
研究领域:
医学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2024
·Vol. 15
·期 10
·1-15
·
IF 8.1
Zhao Rong,Guo Zizhen,Lu Kaikai,Chen Qian,Riaz Farooq,Zhou Yimeng,Yang Luyun,Cheng Xiaona,Wu Litao,Cheng Kexin,Feng Lina,Liu Sitong,Wu Xiaodan,Zheng Minghua,Yin Chunyan,Li Dongmin
Nonalcoholic steatohepatitis (NASH) is a prevalent chronic disease, yet its exact mechanisms and effective treatments remain elusive. Nuclear receptor subfamily 5 group A member 2 (NR5A2), a transcription factor closely associated with cholesterol metabolism in the liver, has been hindered from comprehensive investigation due to the lethality of NR5A2 loss in cell lines and animal models. To elucidate the role of NR5A2 in NASH, we generated hepatocyte-specific knockout mice for Nr5a2 (Nr5a2 HKO ) and examined their liver morphology across different age groups under a regular diet. Furthermore, we established cell lines expressing haploid levels of NR5A2 and subsequently reintroduced various isoforms of NR5A2. In the liver of Nr5a2 HKO mice, inflammation and fibrosis spontaneously emerged from an early age, independent of lipid accumulation. Pyroptosis occurred in NR5A2-deficient cell lines, and different isoforms of NR5A2 reversed this form of cell death. Our findings unveiled that inhibition of NR5A2 triggers pyroptosis, a proinflammatory mode of cell death primarily mediated by the activation of the NF-κB pathway induced by reactive oxygen species (ROS). As a transcriptionally regulated molecule of NR5A2, aldehyde dehydrogenase 1 family member B1 (ALDH1B1) participates in pyroptosis through modulation of ROS level. In conclusion, the diverse isoforms of NR5A2 exert hepatoprotective effects against NASH by maintaining a finely tuned balance of ROS, which is contingent upon the activity of ALDH1B1.
研究领域:
肝病学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death Discovery
·
2024
·Vol. 10
·期 1
·1-16
·
IF 6.1
Liu Zhaohong,Xiang Peng,Zeng Shengmei,Weng Ping,Wen Yilin,Zhang Wanping,Hu Hui,Zhao Dezhang,Ma Limei,Yu Chao
Vascular endothelial injury initiates atherosclerosis (AS) progression. N -Acetylneuraminic acid (Neu5Ac) metabolic disorder was found to intensify endothelial mitochondrial damage. And GLS2-associated glutaminolysis disorder contributed to mitochondrial dysfunction. However, mechanisms underlying Neu5Ac-associated mitochondrial dysfunction as well as its association with GLS2 remains unclear. In this study, we constructed GLS2 −/− ApoE −/− mice by using HBLV-GLS2 shRNA injection. And methods like immunofluorescence, western blotting, transmission electron microscopy were applied to detect profiles of endothelial injury and AS progression both in vivo and in vitro. We demonstrated that Neu5Ac accumulation increased GLS2 expression and promoted glutaminolysis disorder, which further induced endothelial mitochondrial dysfunction via a pyroptosis-dependent pathway in vivo and in vitro. Mechanically, Neu5Ac interacted with SIRT3 and led to FOXO3a deacetylation and phosphorylation, further facilitated c-Myc antagonism and ultimately increased GLS2 levels. Inhibition of GLS2 could improve mitochondrial function and mitigate pyroptosis process. In addition, blocking Neu5Ac production using neuraminidases (NEUs) inhibitor could rescue endothelial damage and alleviate AS development in ApoE −/− mice. These findings proposed that Neu5Ac induced GLS2-mediated glutaminolysis disorder and then promoted mitochondrial dysfunction in a pyroptosis-dependent pathway. Targeting GLS2 or inhibiting Neu5Ac production could prevent AS progression.
研究领域:
心血管疾病
·
分子生物学
·
细胞生物学
·
病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Qiang Zhou,Meiyu Chang,Shuhan Guo,Yiming Zhang,Qiufang Qu,Qingnan Zhou,Zhiheng Li,Sanqiao Yao
Silicosis is a life-threatening occupational disease because of inhaling silica dust, leading to chronic inflammation, pyroptosis, and fibrosis. Unfortunately, it is still lacking effective pharmacological intervention currently. Honokiol ( HKL ), a natural extract with biological activity from Magnolia bark, is known for its antioxidant and anti-inflammatory biological effects. The current work aimed to investigate the therapeutic potential of HKL in mitigating silica-induced lung fibrosis and pyroptosis, particularly focusing on the cGAS/STING signaling pathway. The pulmonary pathological results shown in H&E and Masson’s trichrome staining images confirmed the protective effects of HKL on lung tissue structure. In addition, HKL significantly reduced lung inflammation, collagen deposition, and oxidative stress compared to mice in the silicosis group. HKL treatment also alleviated silica-induced pyroptosis by suppressing the activation of the cGAS/STING signaling pathway in lung tissues. Moreover, the in vitro experiments using J774A.1 macrophages demonstrated that HKL reduced pyroptosis and improved cell viability under exposure to silica combined lipopolysaccharide (LPS). These were attributed to HKL downregulating the activation of the cGAS/STING signaling pathway in pyroptotic J774A.1 cells induced by silica combined with LPS. Meanwhile, inhibition of STING signaling induced by DNase I significantly enhanced the protective effects of HKL on the inflammatory and pyroptotic processes induced by silica. Overall, HKL could attenuate silica-induced pyroptosis by modulating the cGAS/STING signaling pathway against pulmonary fibrosis. The current study offers a promising approach for treating silicosis and related inflammatory responses.
研究领域:
药理学
·
肺病学
·
免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Heliyon
·
2024
·
IF 3.4
Lina Ba,Mingyao E,Ruixuan Wang,Nan Wu,Rui Wang,Renling Liu,Xiang Feng,Hanping Qi,Hongli Sun,Guofen Qiao
Background Cardiac remodeling is a common pathological feature in many cardiac diseases, characterized by cardiac hypertrophy and fibrosis. Triptolide (TP) is a natural compound derived from Tripterygium wilfordii Hook F. However, the related mechanism of it in cardiac remodeling has not been fully understood. Methods and results Transverse aortic constriction (TAC)-induced cardiac hypertrophic mouse model and angiotensin II (Ang II)-induced cardiomyocytes hypertrophic model were performed. Firstly, the results indicate that TP can improve cardiac function, decreased cardiomyocyte surface area and fibrosis area, as well as lowered the protein expressions of brain natriuretic peptide (BNP), β-major histocompatibility complex (β-MHC), type I and III collagen (Col I and III). Secondly, TP suppressed cardiac pyroptosis, and decreased the levels of Interleukin-1β (IL-1β), Interleukin-18 (IL-18) by Enzyme-linked immunosorbent assay (ELISA), and pyroptosis-associated proteins. Furthermore, TP enhanced the expressions of Nuclear factor erythroid 2-related factor 2 (Nrf2) and Heme oxygenase 1 (HO-1). Interestingly, when Nrf2 was silenced by siRNA, TP lost its properties of reducing pyroptosis and cardiac hypertrophy. In addition, in the Transforming Growth Factor β1 (TGF-β1)-induced primary human coronary artery endothelial cells (HCAEC) model, TP was found to inhibit the process of endothelial-to-mesenchymal transition (EndMT), characterized by the loss of endothelial-specific markers and the gain of mesenchymal markers. This was accompanied by a suppression of Slug, Snail, and Twist expression. Meanwhile, the inhibitory effect of TP on EndMT was weakened when Nrf2 was silenced by siRNA. Lastly, potential targets of TP were identified through network pharmacology analysis, and found that Ubiquitin-Specific Protease 14 (USP14) was one of them. Simultaneously, the data indicated that decrease the upregulation of USP14 and Kelch-like ECH-Associated Protein 1 (Keap1) caused by cardiac remodeling. However, Keap1 was decreased and Nrf2 was increased when USP14 was silenced. Furthermore, CoIP analysis showed that USP14 directly interacts with Keap1. Conclusion TP can observably reduce pyroptosis and EndMT by targeting the USP14/Keap1/Nrf2 pathway, thereby significantly attenuating cardiac remodeling.
研究领域:
心脏病学
·
药理学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2026
·
IF 13.6
Shuheng Qin,Mengchu Zhao,Weishu Gao,Ziqi Zhou,Yong Hu,Jiexin Zhang,Jian Xu
High levels of reactive oxygen species (ROS) are critical for inducing efficient pyroptosis. However, conventional sonosensitizers often exhibit limited ROS generation capacity, thereby restricting their pyroptotic efficacy. Herein, we report a PEGylated Fe/Co co-doped MoS 2 nanozyme (FeCo–MoS 2 ) as an advanced sonosensitizer. The incorporation of Fe and Co dopants optimizes the electronic structure of MoS 2 and increases the density of active sites. Under ultrasound (US) stimulation, FeCo–MoS 2 exhibits multi-enzyme mimetic activities, enabling efficient catalysis of endogenous hydrogen peroxide (H 2 O 2 ) into ROS while simultaneously depleting glutathione (GSH). This dual action disrupts intracellular redox homeostasis within the tumor microenvironment, leading to pronounced mitochondrial oxidative stress. In turn, this activates the caspase-1/GSDMD signaling pathway, culminating in controlled pyroptotic cell death. In vitro, FeCo–MoS 2 combined with US treatment markedly induced cell membrane pore formation and elevated release of IL-18 and lactate dehydrogenase (LDH). In vivo studies demonstrated that this system not only suppressed primary and distant tumor growth and prevented lung metastasis, but also triggered the release of damage-associated molecular patterns (DAMPs). This promoted dendritic cell (DC) maturation and enhanced CD8 + T cell infiltration, thereby eliciting a robust and durable anti-tumor immune response. Collectively, our findings highlight a strategy to potentiate pyroptosis and amplify systemic antitumor immunity, offering new insights into nanozyme-enhanced sonodynamic immunotherapy.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2026
·Vol. 20
·期 30
·21403-21422
·
IF 17.3
Yu Wang,Zhao Ru,Miao Liming,Bian Jie,Zhou Yiyao,Zhao Xiaoyu,Song Wei,Wang Yue,Jiang Xiue
Glioblastoma
(GBM) is a highly lethal brain tumor, with
therapeutic
efforts hampered by the restrictive blood–brain barrier (BBB)
and a profoundly immunosuppressive tumor microenvironment (TME). Driven
by bioinformatics analysis identifying epidermal growth factor receptor
(EGFR) and caspase-3 as key regulators of an immune-evasive pyroptosis
pathway, we screened natural compounds and identified quercetin (Q)
and chlorogenic acid (C) as dual-targeting agents, thereby laying
a therapeutic foundation for amplifying pyroptosis in GBM treatment.
The compounds were conjugated into a glutathione-responsive prodrug
(QSSC) and encapsulated in a tumor-derived exosome-liposome nanoplatform
(QSSC@Exo-LNP), enabling enhanced BBB penetration and intracranial
targeting. Mechanistic studies revealed a dual-pathway amplification
of pyroptosis, in which C directly activates caspase-8 to initiate
gasdermin E (GSDME)-mediated pyroptosis, while Q/C-mediated EGFR inhibition
activates mitochondrial pro-apoptotic protein, thereby augmenting
caspase-3 and intensifying pyroptotic cell death. Upon intravenous
injection, QSSC@Exo-LNP triggers robust pyroptosis, releasing DAMPs
and tumor antigens for immune activation and macrophage reprogramming,
converting the TME from “cold” to “hot”
state. Moreover, this treatment strategy can significantly inhibit
the distant tumors in the primary-distal orthotopic GBM model. This
study proposes a strategy for the precise immunotherapy of GBM by
exploiting natural products to target overexpressed GSDME and induce
the pyroptotic cascade.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
·
2026
·Vol. 63
·期 1
·837
·
IF 5.5
Wang Yan,Yuan Bin,Li Yunzi,Sun Yan,Xie Yi,Cheng Hao,Zhang Yao,Wu Qi,Tang Jun
Neuropathic pain (NP) presents a significant challenge for patients with chronic diseases, characterized by spontaneous pain and hyperalgesia, with recent studies highlighting the involvement of the gut microbiota in its pathogenesis. Increasing evidence suggests that melatonin mitigates systemic inflammation and remodels gut microbiota. The present study further explored the mechanism by which oral melatonin ameliorates pain-related behavior following peripheral nerve injury. In this study, mice with chronic constriction injury (CCI) were orally administered melatonin (100 mg/kg) for 14 days. Pain behaviors were evaluated using mechanical allodynia and thermal hyperalgesia tests. Gut microbiota profiles were assessed via 16S rRNA sequencing, and microbiota-dependent effects were verified through antibiotic treatment (ABX) and fecal microbiota transplantation (FMT). Linoleic acid (LA) levels in serum and spinal cord were measured using liquid chromatography–mass spectrometry (LC–MS), and protein expression of NLRP3, caspase-1, and GSDMD in spinal cord tissue was examined by immunoblotting. Melatonin treatment significantly increased the mechanical pain threshold and prolonged thermal withdrawal latency in CCI mice. It also remodeled the dysbiotic gut microbiota, and these protective effects were abolished by antibiotic treatment but restored by FMT. Protein analysis revealed upregulation of NLRP3 and GSDMD in CCI mice, both of which were suppressed following melatonin administration. Moreover, melatonin-induced microbiota modulation elevated LA levels in serum and spinal cord. Supplementation with LA alone alleviated NP and inhibited NLRP3, caspase-1, and GSDMD activation. These findings suggest that oral melatonin treatment effectively ameliorates NP in CCI mice associated with the neuroinflammation and microbiota-metabolites-brain axis.
✓ 已验证
产品关联
DOI
高影响因子
Materials Today Bio
·
2026
·
IF 11
Pan Zhang,Minglun Liu,Lei Huang,Zijie Zhao,Qianqian Zhang,Yunhao Li,Yuncong Chen,Lili Liang
Triple-negative breast cancer (TNBC) frequently exhibits profound chemoresistance and a highly immunosuppressive tumor microenvironment (TME), leading to suboptimal clinical outcomes with high risks of early recurrence and distant metastasis. Existing monotherapies remain inadequate in disrupting these therapeutic barriers. To overcome the aforementioned obstacles, we developed a spatiotemporally regulated organelle-targeted nanoplatform, IR820-GEM@MIL101 (IGM), Its design aims to achieve precise mitochondrial intervention and coordinate cGAS–STING-mediated immune activation. This design relies on EPR-mediated passive targeting to achieve preferential tumor accumulation, allowing IGM to accumulate specifically in tumor tissues and trigger a series of reactions in response to endogenous stimuli (acidic pH and elevated glutathione) in synergy with exogenous near-infrared laser activation, enabling controlled drug release. The platform efficiently eliminates tumor cells by inducing multiple modes of cell death, including pyroptosis, ferroptosis, and apoptosis, while simultaneously triggering immunogenic cell death (ICD) and activating the cGAS–STING pathway. This dual immunostimulatory strategy effectively converts “cold” tumors into “hot” tumors. In a bilateral tumor model, IGM treatment increased CD8 + T-cell infiltration in distal tumors by 94% and achieved a tumor inhibition rate of 92.7% in distant lesions. This work shifts the therapeutic focus from superficial multi-drug packaging to precise organelle-targeted intervention, providing a promising strategy for light-regulated combinatorial immunotherapy against aggressive malignancies.
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）