PHYTOMEDICINE
·
2024
·
IF 6.7
Shuang Chai,Yanbing Yang,Liwei Wei,Yuju Cao,Jiangtao Ma,Xuxia Zheng,Junyan Teng,Na Qin
Background Recently, osteoblast pyroptosis has been proposed as a potential pathogenic mechanism underlying osteoporosis, although this remains to be confirmed. Luteolin (Lut), a flavonoid phytochemical, plays a critical role in the anti-osteoporosis effects of many traditional Chinese medicine prescriptions. However, its protective impact on osteoblasts in postmenopausal osteoporosis (PMOP) has not been elucidated. Purpose This research aimed to determine the effect of Lut in ameliorating PMOP by alleviating osteoblast pyroptosis and sustaining osteogenesis. Study design This research was designed to investigate the novel mechanism of Lut in alleviating PMOP both in cell and animal models. Methods Ovariectomy-induced PMOP models were established in mice with/without daily gavaged of 10 or 20 mg/kg body weight Lut. The impact of Lut on bone microstructure, metabolism and oxidative stress was evaluated with 0.104 mg/kg Estradiol Valerate Tablets daily gavaged as positive control. Network pharmacological analysis and molecular docking were employed to investigate the mechanisms of Lut in PMOP treatment. Subsequently, the impacts of Lut on the PI3K/AKT axis, oxidative stress, mitochondria, and osteoblast pyroptosis were assessed. In vitro, cultured (MC3T3-E1(14) cells were exposed to H 2 O 2 with/without Lut to examine its effects on the PI3K/AKT signaling pathway, osteogenic differentiation, mitochondrial function, and osteoblast pyroptosis. Results Our findings demonstrated that 20 mg/kg Lut, similar to the positive control drug, effectively reduced systemic bone loss and oxidative stress, and enhanced bone metabolism induced by ovariectomy. Network pharmacological analysis and molecular docking indicated that the PI3K/AKT axis was a potential target, with oxidative stress response and nuclear membrane function being key mechanisms. Consequently, the effects of Lut on the PI3K/AKT axis and pyroptosis were investigated. In vivo data revealed that the PI3K/AKT axis was deactivated following ovariectomy, and Lut restored the phosphorylation of key proteins, thereby reactivating the axis. Additionally, Lut alleviated osteoblast pyroptosis and mitochondrial abnormalities induced by ovariectomy. In vitro, Lut intervention mitigated the inhibition of the PI3K/AKT axis and osteogenesis, as well as H 2 O 2 -induced pyroptosis. Furthermore, Lut attenuated ROS accumulation and mitochondrial dysfunction. The effects of Lut, including osteogenesis restoration, anti-pyroptosis, and mitochondrial maintenance, were all reversed with LY294002 (a PI3K/AKT pathway inhibitor). Conclusion In summary, Lut could improve mitochondrial dysfunction, alleviate GSDME-mediated pyroptosis and maintain osteogenesis via activating the PI3K/Akt axis, offering a new therapeutic strategy for PMOP.
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Cell Reports
·
2024
·
IF 7.5
Xueping Li,Jiarui Zhou,Xingmei Liu,Chen Jin,Le Liu,Hongmin Sun,Qian Wang,Qiushi Wang,Ruiying Liu,Xiaoyu Zheng,Yutao Liu,Yu Pang
Uropathogenic Escherichia coli (UPEC) is the most common causative agent of urinary tract infection (UTI). UPEC invades bladder epithelial cells (BECs) via fusiform vesicles, escapes into the cytosol, and establishes biofilm-like intracellular bacterial communities (IBCs). Nucleoside-diphosphate kinase (NDK) is secreted by pathogenic bacteria to enhance virulence. However, whether NDK is involved in UPEC pathogenesis remains unclear. Here, we find that the lack of ndk impairs the colonization of UPEC CFT073 in mouse bladders and kidneys owing to the impaired ability of UPEC to form IBCs. Furthermore, we demonstrate that NDK inhibits caspase-1-dependent pyroptosis by consuming extracellular ATP, preventing superficial BEC exfoliation, and promoting IBC formation. UPEC utilizes the reactive oxygen species (ROS) sensor OxyR to indirectly activate the regulator integration host factor, which then directly activates ndk expression in response to intracellular ROS. Here, we reveal a signaling transduction pathway that UPEC employs to inhibit superficial BEC exfoliation, thus facilitating acute UTI.
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BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Jian Zhang,Xinlin Li,Wenqing Cui,Dingchun Lu,Yanyan Zhang,Jiajia Liao,Linlin Guo,Chunen Jiao,Ling Tao,Yini Xu,Xiangchun Shen
Accumulating evidence strongly support the key role of NLRP3-mediated pyroptosis in the pathogenesis and progression of vascular endothelial dysfunction associated with diabetes mellitus. Various studies have demonstrated that the activation or upregulation of Silent Information Regulation 2 homolog 2 (SIRT2) exerts inhibitory effect on the expression of NLRP3. Although 1,8-cineole has been found to protect against endothelial dysfunction and cardiovascular diseases, its role and mechanism in diabetic angiopathy remain unknown. Therefore, the aim of this study was to investigate the ameliorative effect of 1,8-cineole through SIRT2 on pyroptosis associated with diabetic angiopathy in human umbilical vein endothelial cells (HUVECs) and to elucidate the underlying mechanism. The findings revealed that 1,8-cineole exhibited a protective effect against vascular injury and ameliorated pathological alterations in the thoracic aorta of diabetic mice. Moreover, it effectively mitigated pyroptosis induced by palmitic acid-high glucose (PA-HG) in HUVECs. Treatment with 1,8-cineole effectively restored the reduced levels of SIRT2 and suppressed the elevated expression of pyroptosis-associated proteins. Additionally, our findings demonstrated the occurrence of NLRP3 deacetylation and the physical interaction between NLRP3 and SIRT2. The SIRT2 inhibitor AGK2 and siRNA-SIRT2 effectively attenuated the effect of 1,8-cineole on NLRP3 deacetylation in HUVECs and compromised its inhibitory effect against pyroptosis in HUVECs. However, overexpression of SIRT2 inhibited PA-HG-induced pyroptosis in HUVECs. 1,8-Cineole inhibited the deacetylation of NLRP3 by regulating SIRT2, thereby reducing pyroptosis in HUVECs. In conclusion, our findings suggest that PA-HG-induced pyroptosis in HUVECs plays a crucial role in the development of diabetic angiopathy, which can be mitigated by 1,8-cineole.
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Journal of Ovarian Research
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2025
·Vol. 18
·期 1
·1-16
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IF 4.2
Chen Sailing,Lu Han,Ying Yingfen,Xi Haitao,Zheng Jingyi,Gong Chaochao,Wang Shaowei,Tang Yunbin,Zhao Junzhao,Ge Ren-shan,Li Xiaoheng
Section
Background
Polycystic ovary syndrome (PCOS) is a common endocrine disorder with significant impacts on women’s reproductive health. Interleukin (IL)-2 receptor subunit gamma (IL2RG), a common receptor for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, has been shown to interrupt estrous cycle, yet its role in PCOS remains unclear.
Section
Results
The evaluated expression levels of IL2RG in human granulosa cells (GCs) and IL2RG-dependent cytokines (IL-2, IL-4, IL-15) in follicular fluid were demonstrated in 18 PCOS patients and 22 control subjects. The positive correlation between IL2RG and PCOS was analysed through GEO databases. In vivo, we found that in the PCOS model (6 mg/100 g body-weight of dehydroepiandrosterone subcutaneous injection for 21 days), the ovarian index, testosterone, glucose, and LH/FSH levels were elevated, and the estrous cycle was disrupted. Knocking down IL2RG (KO) restored the above levels. However, in the dehydroepiandrosterone-treated group, these levels did not recover even after IL2RG was knocked-down. The decreased expression of Gasdermin E (GSDME) but increased caspase-3 level in IL2RG KO rats compared with WT were found. In vitro, knockdown of IL2RG by siRNA inhibited caspase-3-mediated GSDME cleavage in testosterone-induced KGN cells. Furthermore, the caspase-3 inhibitor Z-DEVD-FMK and the caspase-1 inhibitor Belnacasan alleviated pyroptosis in testosterone-induced KGN cells by lactate dehydrogenase test, fluorescence assay, and flow cytometry.
Section
Conclusion s
IL2RG is expressed higher in PCOS patients, exerting an inhibitory effect on caspase-3-mediated GSDME cleavage upon knockdown. However, the knockout of IL2RG led to the conversion of GSDME-mediated pyroptosis into apoptosis. This study explores the function of IL2RG and provides insights for therapeutic targets in PCOS.
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NEUROPHARMACOLOGY
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2025
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IF 4.6
Yang Wang,Zhihan Wan,Ning Wang,Qian Wu,Saiwang Seto
Pyroptosis is a type of proinflammatory programmed cell death, that closely related to the progress of cerebral ischemia / reperfusion injury (CIRI), and NLRP3 inflammasome is the most classic pathway mediating pyroptosis. Ligustilide (LIG) is a natural compound derived from the traditional Chinese herb chuanxiong hort and angelica sinensis which can penetrate the blood-brain barrier and has a good neuroprotective effect. However, it remains unclear whether LIG could alleviate CIRI by inhibiting pyroptosis. Here, the neuroprotective effect of LIG was verified by reducing NLRP3-mediated pyroptosis, and further exploring whether the inhibition of LIG on pyroptosis was related to Nuclear factor-erythropoietin 2-related factor 2(Nrf2)activation. The results showed that LIG can reduce the injury of brain tissue after ischemia, as well as NLRP3 inflammasome-mediated pyroptosis and neuroinflammation response after MCAO/R in rats. Mechanistically, the effect of LIG on Nrf2 was detected by molecular docking, protein levels and immunofluorescence analysis. We found that LIG promoted the Nrf2 expression and reduced the production of mitochondrial ROS (mtROS), and than inhibited NLRP3 inflammasome-mediated pyroptosis. Particularly revealing was that ML385, the inhibitor of Nrf2, partly blocked the above effects of LIG. All these findings suggest that LIG may ameliorate CIRI through inhibiting NLRP3 inflammasome-mediated pyroptosis dependent on Nrf2 signaling.
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MOLECULAR PHARMACEUTICS
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2025
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IF 4.5
Ying Yin,Xiang Cheng,Duoyang Fan,Yanpeng Fang,Haohan Li,Xingru Zhou,Hongqi Guo,Wenbin Zeng,Fei Chen
Photodynamic therapy (PDT), a noninvasive and spatiotemporally controlled cancer treatment, often suffers from the mitochondrial or lysosomal accumulation of conventional photosensitizers (PSs), primarily triggering apoptosis and limiting efficacy against apoptosis-resistant tumors. Targeting the plasma membrane offers a promising, yet less explored, strategy to induce immunogenic cell death pathways like ferroptosis and pyroptosis, which can overcome therapeutic resistance. However, PSs capable of simultaneously targeting the plasma membrane and activating both ferroptosis and pyroptosis are scarce. Here, we present a simple and rational π-bridge engineering strategy to develop multifunctional membrane-anchored PSs. Among our synthesized compounds, TDTP exhibits strong near-infrared (NIR) fluorescence, distinct aggregation-induced emission (AIE) characteristics, superior reactive oxygen species (ROS) generation, and precise plasma membrane localization. Upon light activation, TDTP induces synergistic ferroptotic-pyroptotic cell death, leading to highly efficient tumor ablation at nanomolar concentrations (IC50 = 26.07 nM). In vivo studies demonstrate that TDTP enables high-contrast NIR imaging and substantially inhibits tumor growth under image-guided PDT. This work highlights a facile yet powerful strategy for constructing membrane-specific PSs and introduces a rare class of theranostic agents capable of inducing dual cell death pathways.
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Cell Death & Disease
·
2025
·Vol. 16
·期 1
·1-11
·
IF 9.6
Chu Xiufeng,Zhang Ting,Bukhari Ihtisham,Hu Mei,Xu Jixuan,Xing Yamin,Liang Xinfeng,Zhang Zisen,Zheng Pengyuan
Gasdermin D (GSDMD) is a critical pyroptosis mediator, consisting of one N-terminal pore-forming domain and one C-terminal auto-inhibitory domain. The free N-terminal domain (GD-NT), which is released through caspase-1/11 cleavage, exhibits distinct features from the full-length GSDMD (GD-FL), including oligomerization, membrane translocation, and pore-formation. However, the underlying mechanisms are not well elucidated. Here, we found that GD-NT, but not GD-FL, was massively ubiquitinated in cells. The K63-linked polyubiquitination of GD-NT at Lys236/237 (human/mouse), catalyzed by TRAF1, directly prompted its membrane translocation and pore-formation during pyroptosis. Inhibition of GD-NT ubiquitination via site-directed mutations or the UBA1 inhibitor PYR-41 suppressed cell death in several pyroptosis cell models. Additionally, applying PYR-41 in septic mice efficiently suppressed the release of IL-18 and TNFα. Thus, GD-NT ubiquitination is a key regulatory mechanism controlling its membrane localization and activation, which may provide a novel target for modulating immune activity in pyroptosis-related diseases.
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ACS Nano
·
2024
·
IF 15.8
Youdong Chen,Yujie Lu,Huali Lei,Lin Liu,Xianmin Li,Yuqi Yang,Shumin Sun,Qiao Yu,Li Wang,Jie Wu,Jingrui Li,Guanghui Hou,Liang Cheng
Immunotherapy holds significant promise for cancer treatment. However, the highly immunosuppressive nature of solid tumors limits its effectiveness. Herein, we developed bioactive zinc–nickel hydroxide (ZnNi(OH)4) nanosheets (NSs) that can effectively initiate the paraptosis–pyroptosis positive feedback cycle through synergistic ionic effect, thereby mitigating the immunosuppression of solid tumors and enhancing the efficacy of immunotherapy. The acid-sensitive ZnNi(OH)4 NSs releases Ni2+ and Zn2+ in the weakly acidic tumor microenvironment. The released Ni2+ alleviated pyroptosis inhibition by inducing paraptosis and inhibiting autophagic flux. Concurrently, Ni2+ triggered release of endogenous Zn2+ within the cell through a coordination competition mechanism, further amplifying zinc overload-mediated pyroptosis. Interestingly, pyroptosis-associated oxidative stress and endoplasmic reticulum stress further promote Ni2+-mediated paraptosis, forming a positive feedback loop between pyroptosis and paraptosis. This process not only effectively kills tumor cells but also stimulates a strong inflammatory response, enhancing the antitumor immune response and immunotherapy efficacy. Overall, this study proposes an effective paraptosis–pyroptosis induction strategy based on metal ions and demonstrates the effectiveness of the positive feedback loop of paraptosis–pyroptosis in potentiating immunotherapy.
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MOLECULAR BIOLOGY REPORTS
·
2025
·Vol. 53
·期 1
·82
·
IF 2.8
Qi Xue,Hu Yanjun,Yang Jinghan,Jiang Mingxuan,Zhang Junhao,Du Yanting,Hu Changmin
Background The pathogenesis of bovine mastitis involves inflammation and cell death, with pyroptosis being a key factor in its development. Currently, antibiotics remain the primary therapeutic option for bovine mastitis, however, the increasing prevalence of antibiotic resistance constitutes a major public health threat. Selenium (Se) has been reported to alleviate inflammation primarily through its antioxidant properties, but the mechanism by which Se regulates pyroptosis in bovine mastitis remains unclear. Methods and results In this study, an in vitro mastitis model was established by infecting MAC-T cells with inactivated Staphylococcus aureus ( S. aureus ) (MOI = 10, 12 h). The results revealed that the mitochondrial membrane potential of the MAC-T cells in the infection group decreased significantly. Moreover, the accumulation of Reactive oxygen species (ROS) was accompanied by the activation of NOD-like receptor family containing pyrin domain 3 (NLRP3), the expression of the pyroptosis-related genes gasdermin D amino terminal fragment (GSDMD-N), and cysteine aspartate specific protease 1 (cleaved-caspase 1). Pretreatment with Se, the NLRP3 inhibitor MCC950 and the antioxidant N-acetylcysteine (NAC) attenuated mitochondrial damage, ROS accumulation, and the inhibition of pyroptosis. An in vivo mastitis model was established in mice fed a high-selenium diet (containing 1.5 mg/kg Se) and intramammarily injected with inactivated S. aureus (1 × 10 8 CFU/mL). Histological analysis revealed intact alveolar structure and reduced inflammatory cell infiltration in mice fed the high-selenium diet. The expression of the inflammasome NLRP3 downregulated, and the expression of GSDMD-N, a direct executor of pyroptosis, upregulated. Conclusion Our in vitro and in vivo results confirmed that Se alleviate mitochondrial damage and pyroptosis by inhibiting the NLRP3 pathway, ultimately alleviating mastitis. Graphical
研究领域:
兽医学
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免疫学
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分子生物学
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炎症与感染
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营养与代谢
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ACS Applied Nano Materials
·
2026
·
IF 5.8
Guanheng Wang,Lin Li,Biao Xue,Yu Li,Yaling Zhang,Jiapeng Wang,Yulei Cui,Chunlei Li,Xiuwen Zheng
In this study, a pH-responsive Cu-doped zeolitic imidazolate framework-8 nanoplatform was coloaded with paclitaxel and doxorubicin for synergistic tumor therapy. Hyaluronic acid modification on the outer surface of the nanomaterials enhances tumor targeting via CD44 receptor-mediated endocytosis. ZIF-8, derived from metal–organic frameworks, is an excellent nanocapsulator capable of specifically responding to the acidic tumor microenvironment. Upon reaching the tumor site, it rapidly degrades, releasing copper ions and chemotherapeutic drugs to exert antitumor effects. Copper ions consume endogenous hydrogen peroxide and glutathione through Fenton-like reactions, thereby generating cytotoxic reactive oxygen species, enhancing chemodynamic therapy efficiency, and inducing cuproptosis. The released PTX and DOX not only exert chemotherapeutic effects but also induce pyroptosis by activating the classical pathway mediated by caspase-3 and Gasdermin E. Due to excessive activation of the Wnt/β-catenin signaling pathway, PTX faces drug resistance in the treatment of triple-negative breast cancer, whereas DOX can inhibit this pathway by promoting β-catenin degradation. These therapies act synergistically to trigger immunogenic cell death, release damage-associated molecular patterns, promote dendritic cell maturation, activate T cells, and effectively reshape the immunosuppressive tumor microenvironment. This multimodal nanoplatform demonstrates remarkable potential as an antitumor treatment.
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Molecular Medicine Reports
·
2026
·Vol. 33
·期 4
·1-14
·
IF 5
Xiaoyu Zheng,Jinping Li,Tianyang Hu,Li Tan,Ding Lan,Ying Deng
Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Xizhi Li,Tingting Zhou,Yixi Wu,Jiayi Sun,Ziyu Wang,Yuhan Huang,Ke Xu,Hongwei Ling,Na Li,Tingting Yang,Tao Wang
Exenatide, the first glucagon-like peptide-1 receptor agonist (GLP-1RA), exerted multiple beneficial effects, including stimulating insulin secretion, slowing gastric emptying, and improving insulin resistance (IR). Our previous work demonstrated that the peroxisome proliferator-activated receptor delta (PPARδ) gene ( PPARD ) polymorphisms correlated with exenatide monotherapy efficacy, possibly due to the pivotal role of PPARδ in regulating IR. Specifically, PPARδ has been shown to modulate the nucleotide-binding domain and leucine-rich repeat pyrin domain-containing 3 (NLRP3) inflammasome, a key regulator of pyroptosis, thereby participating in the regulation of this inflammatory cell death pathway. However, the underlying mechanisms by which exenatide ameliorated hepatic IR in patients with type 2 Diabetes Mellitus (T2DM) remained incompletely understood. Herein, we found that exenatide suppressed pyroptosis and ameliorated hepatic IR; furthermore, it could bind to PPARδ and upregulate PPARδ protein expression both in vitro and in vivo. Notably, PPARδ knockdown abolished the protective effects of exenatide against pyroptosis and hepatic IR, whereas pharmacological activation of PPARδ enhanced these beneficial effects. Moreover, T2DM patients carrying the AA genotype at PPARD rs3777744 and exhibiting higher baseline homeostasis model assessment of insulin resistance (HOMA-IR) showed a superior response to exenatide. Collectively, our findings revealed that exenatide ameliorated hepatic IR by suppressing pyroptosis via PPARδ, underscoring the potential of PPARD rs3777744 as a biomarker for personalized exenatide therapy in T2DM.
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