JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Chenhan He,Peipei Zhou,Zhibo Zhang,Tongyin Yan,Liwei Liu,Yaojuan Chu,Lihua Zuo,Fanmei Zou,Linguo Zhao,Yifei Wang,Shuzhang Du,Zhi Sun
Ethnopharmacological relevance Thromboangiitis obliterans (TAO) is a necrotic lesion with complex inflammatory changes in the vessel wall. Mailuo Shutong pill (MLSTP), a traditional Chinese medicine formula (TCM) clinically prescribed for TAO, has been proven to possess good efficacy in treating TAO. However, the underlying mechanism of its action remains unclear. Aim of the study To explore the mechanism of MLSTP in alleviating the sodium laurate-induced thromboobliteration using lipidomics and bioinformatics analysis. Methods UHPLC-Q-Orbitrap-HRMS was used to identify compounds of MLSTP. Clinical score, pathological picture of gangrene, and hematoxylin-eosin staining were used to evaluate the antithrombin effect of MLSTP on the TAO model. Lipidomics was used to discover core biomarkers and lipid metabolism. The causal links between core biomarkers and compounds were forecast via bioinformatics analysis and verified through immunohistochemical stainings. Results Eighty-five and fourteen prototype components were successfully identified in the plasma and right posterior femoral arteries, respectively. Pharmacodynamic studies suggested that MLSTP could exert noticeable vasoprotective effects on TAO rats. Moreover, twenty-three differential metabolites were found with sphingolipid metabolism, glycerolipid metabolism, linoleic acid metabolism, and alpha-linolenic acid metabolism. Besides, bioinformatics analysis predicted the pyroptosis genes associated with sphingolipid metabolism. Subsequently, the immunohistochemical analysis revealed that aberrant CerS1 overexpression in femoral arteries initiates sphingolipid metabolic dysregulation, which subsequently activates the CASP8/CASP3/GSDME-mediated pyroptosis pathway and drives overexpression of inflammatory cytokines (IL-1β, IL-18, TNF-α, IL-6). Integrating component identification, lipidomics, and bioinformatics analysis identified four lipid metabolism pathways and one pyroptosis pathway related to sphingolipid metabolism, which revealed multiple mechanisms of MLSTP against TAO involving remedying lipid disturbances and pyroptosis. Conclusions MLSTP alleviated sodium laurate-induced thromboobliteration by rectifying lipid homeostasis imbalance and inhibiting potential pyroptosis pathways. More importantly, it offered new perspectives on the mechanism of TAO.
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Annals of Translational Medicine
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2022
·Vol. 10
·期 20
·1101-1101
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IF 3.616
Jiangyan He,Yiyuan Zhou,Taiwei Zhang,Yan Zou,Hua Huang
Background Subclinical hypothyroidism (SH) is common during pregnancy. It is not clear whether decidual cells in SH undergo pyroptosis during pregnancy. This study aimed to investigate the possible mechanism of Bushen Antai recipe (BAR) in the treatment of SH in early pregnancy and the relationship between SH during pregnancy and decidual cell pyroptosis through a rat model. Methods A total of 60 female rats were divided into control group, model group, levothyroxine (L-T4) group, low-dose BAR group (6 g/kg), medium-dose BAR group (12 g/kg), and high-dose BAR group (24 g/kg). The control group underwent pseudothyroidectomy, while the remaining groups established nonpregnant SH rat models. Except for the blank control group, rats were successfully established with SH models during pregnancy. The control group and the model group were treated with saline or BAR. The animals were sacrificed 12 hours after the last administration. The levels of serum thyroid-stimulating hormone (TSH), free thyroxine (FT4), interleukin-1β (IL-1β), and interleukin-18 (IL-18) were detected by enzyme-linked immunosorbent assay (ELISA). Western blot was used to detect the expression of decidual nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome, Caspase-1, and porin family proteins. Results There was no significant difference in serum FT4 among groups (P>0.05). Compared with the control group, serum TSH, IL-1β, IL-18, and NLRP3, Caspase-1, and gasdermin D (GSDMD) proteins in the decidua of the model group were significantly increased (P<0.05). Compared with the model group, the L-T4 group and the high-dose BAR group could significantly decrease the levels of serum TSH, IL-1β, IL-18, and NLRP3, Caspase-1, and GSDMD in decidual tissue (P<0.05). The medium dose of BAR could significantly decrease the levels of TSH, NLRP3, Caspase-1, and GSDMD (P<0.05), and the low dose group of BAR significantly decreased the levels of TSH, NLRP3, and GSDMD (P<0.05). Among them, the high-dose group of BAR had the best reducing effect on IL-18, NLRP3, Caspase-1, and GSDMD. Conclusions The decidual cells of SH rats in early pregnancy underwent pyroptosis with a high inflammatory response. BAR could improve TSH level in SH during pregnancy, inhibit decidual cell pyroptosis, and reduce the expression of inflammatory factors.
研究领域:
内分泌学
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妇产科学
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药理学
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免疫学
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Journal of Advanced Research
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2020
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IF 6.992
Qinghai Meng,Yu Li,Tingting Ji,Ying Chao,Jun Li,Yu Fu,Suyun Wang,Qi Chen,Wen Chen,Fuhua Huang,Youran Wang,Qichun Zhang,Xiaoliang Wang,Huimin Bian
Introduction Excessive inflammation and the pyroptosis of vascular endothelial cells caused by estrogen deficiency is one cause of atherosclerosis in post-menopausal women. The autophagy is highly regulated by estrogen, however whether estrogen can reduce vascular endothelial cell pyroptosis through estrogen receptor-mediated activation of autophagy to improve atherosclerosis in post-menopausal stage is still unknown. Objectives To explore whether estrogen can prevent atherosclerosis by regulating estrogen receptor and subsequently activating autophagy to reduce inflammation and pyroptosis. Methods Aortic samples from pro-menopausal and post-menopausal women with ascending aortic arteriosclerosis were analyzed, and bilateral ovariectomized (OVX) female ApoE-/- mice and homocysteine (Hcy)-treated HUVECs were used to analyze the effect of estrogen supplementation therapy. Results The aortic endothelium showed a decrease in ERα expression and autophagy, but presented an increase in inflammation and pyroptosis in female post-menopausal patients. Estrogen treatment accelerated autophagy and ameliorated cell pyroptosis in the cardiac aortas of OVX ApoE-/- mice and Hcy-treated HUVECs. Estrogen had therapeutic effect on atherosclerosis and improved the symptoms associated with lipid metabolism disorders in OVX ApoE-/- mice. Inhibition and silencing of ERα led to a reduction in the autophagy promoting ability of estrogen and aggravated pyroptosis. Moreover, the inhibition of autophagy promoted pyroptosis and abolished the protective effect of estrogen, but had no influence on ERα expression. Conclusion The results of the present study demonstrated that post-menopausal women present decreased autophagy and ERα expression and excessive damage to the ascending aorta. In addition, in vitro and in vivo assay results demonstrated that estrogen prevents atherosclerosis by upregulating ERα expression and subsequently induces autophagy to reduce inflammation and pyroptosis.
研究领域:
心血管疾病
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内分泌学
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分子生物学
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细胞生物学
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Frontiers in Bioengineering and Biotechnology
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2022
·
IF 6.064
Yu Zhu,Cao Wenlong,Han Chuangye,Wang Zhen,Qiu Yue,Wang Jiancheng,Wei Mengda,Wang Junfu,Zhang Siwen,Liu Senfeng,Mo Shutian,Chen Junqiang
In recent years, sonodynamic therapy (SDT) has been widely developed for cancer research as a promising non-invasive therapeutic strategy. Here, we synthesized zeolitic imidazole frameworks-8 (ZIF-8) and utilized its properties to encapsulate hydrophobic Chlorin e6 (Ce6) and hydrophilic tirapazamine (TPZ) for a synergistic sonodynamic chemotherapy, which was also accompanied by the modification of cytomembrane of gastric cancer (GC) cells. Thus, we enabled the biomimetic property to achieve targeted delivery. Ce6-mediated SDT, in combination with ultrasound irradiation, could target the release of reactive oxygen species (ROS) to aggravate further hypoxia and activate TPZ. Combining these effects could induce the pyroptosis of GC cells and play the anti-tumor function, which could provide a potential therapeutic method for cancer therapy.
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FREE RADICAL BIOLOGY AND MEDICINE
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2021
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IF 7.376
Rong Fan,Jidong Sui,Xuepeng Dong,Biao Jing,Zhenming Gao
Acute pancreatitis (AP) is an inflammatory disorder associated with multiple organ failure . Pyroptosis and ferroptosis are two newly recognized cell death , and whether pyroptosis and ferroptosis are involved in AP remain largely elusive. The nature compound Wedelolactone (Wed) exhibits strong anti-inflammatory and antioxidant activities , the present study aims to investigate the effect of Wed on AP and unravel whether Wed could protect against AP and relevant lung injury against pyroptosis and ferroptosis. Our results showed that the pyroptosis inhibitor disulfiram or ferroptosis inhibitor ferrostatin-1 significantly alleviated AP and associated lung injury in the taurocholate or caerulein-induced murine AP model. Administration with Wed ameliorated AP and lung injury as evidenced by improved pathological injuries, reduced serum pancreatic digestive enzymes , and proinflammatory cytokines . The in vivo and in vitro data demonstrated that Wed broadly inhibited caspase1/caspase11 activation, reduced mature interleukin-1β (IL-1β) and N-terminal domain of gasdermin D (GSDMD-N) level. The oxidative stress and lipid peroxidation were also suppressed along with the up-regulation of the ferroptosis antagonism marker glutathione peroxidase-4 (GPX4) in Wed treatment group. Wed promoted the transcriptional activity and the selenium sensitivity of GPX4. Moreover, the protective effects of Wed in caerulein-stimulated pancreatic acinar cells were markedly abrogated by the down-regulation of GPX4. Collectively, our data suggest that pyroptosis and ferroptosis play crucial roles in AP. Wed mitigated AP and associated lung injury via GPX4 mediated suppression of pyroptosis and ferroptosis.
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PHYTOMEDICINE
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2023
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IF 7.9
MinChao Feng,BaiJun Qin,Fang Luo,Hui Li,KunRong Liu,Kai Li,DongYang Wu,XiPing Tang,Guozhong Chen
Background Safer and more effective drugs are needed for the treatment of acute pancreatitis (AP). Qingjie Huagong decoction (QJHGD) has been applied to treat AP for many years and has shown good clinical effects. However, the potential mechanism has not yet been determined. Purpose To investigate the role and underlying mechanism of the effects of QJHGD on AP both in vitro and in vivo . Methods QJHGD was characterized by UHPLC-Q-Orbitrap-MS. The protective effect of QJHDG and the underlying mechanism were investigated in MPC-83 cells in vitro . A caerulein-induced AP model was established to evaluate the protective effect of QJHGD in mice. CCK-8 assays were used to detect cell viability. The contents of inflammatory mediators were determined by ELISA. Expression levels of circRNA, miRNA and mRNA were determined by qRT-PCR. Protein expression was determined using Western blot . Pancreatic tissues were assessed by hematoxylin and eosin staining as well as immunohistochemical and immunofluorescence analyses. Pull-down and luciferase activity assays were performed to determine the regulatory relationships of circHipk3, miR-193a-5p and NLRP3. Results Our results confirmed that mmu-miR-193a-5p was sponged by mmu-circHipk3, and NLRP3 was a target of miR-193a-5p. In vitro experiments showed that QJHGD enhanced MPC-83 cell viability by regulating circHipk3 sponging mir-193a-5 targeting NLRP3 and inhibiting pyroptosis-related factors. Finally, we showed that QJHGD ameliorated pancreatic tissue injury in AP mice via this pathway. Conclusion This study demonstrate that QJHDG exerted its anti-AP effects via the circHipk3/miR-193a-5p/NLRP3 pathway, revealing a novel mechanism for the therapeutic effect of QJHDG on AP.
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ANTIOXIDANTS & REDOX SIGNALING
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2019
·Vol. 30
·期 12
·1503-1520
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IF 5.828
Tingting Chen,Yichen Guo,Jinjun Shan,Jiarui Zhang,Xu Shen,Jun Guo,Xiaoguang Margaret Liu
Aims: Pyroptotic cells are characterized by plasma swelling, membrane blebbing, and disintegration of the cell membrane mediated by spectrin-based membrane skeleton and intercellular competitive tension activities. The spectrin-based membrane skeleton is involved in membrane organization through the regulation of intercellular tension. Using genetically encoded tension sensors to attain noninvasive force measurements in structural proteins, we investigated how cytoskeletal structural tension influences changes in plasma morphology during pyroptosis and the regulatory mechanism of cytoskeletal structural tension that underpins pyroptosis.Results: The results indicate that increasing spectrin tension is caused by osmotic swelling. Hightened tension of spectrin was closely associated with the shrink tension transmitted synergistically by microfilaments (MFs) and microtubules (MTs). However, the increment of spectrin tension in pyroptotic cells was controlled antagonistically by MF and MT forces. Different from MF tension, outward MT forces participated in the formation of membrane blebs. Spectrin tension caused by inward MF forces resisted pyroptosis swelling. Stabilization of MF and MT structure had little influence on intracellular tension and pyroptosis deformation. Pyroptosis-induced cytoskeletal structural tension was highly dependent on calcium signaling and reactive oxygen species generation. Blocking of membrane pores, nonselective ion flux, or elimination of caspase-1 cleavage resulted in the remission of structural forces associated with pyroptosis failure.Innovation and Conclusions: The data suggest that subcellular tension, in terms of magnitude and vector, is integral to pyroptosis through the mediation of swelling and blebbing and the elimination of structural tension, especially MT forces, may result in pyroptosis inhibition.
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Food & Function
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2024
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IF 5.1
Meitong Liu,Jiakang Guo,Jing Lu,Yuelin Chen,Xuming Deng,Shengzhuo Zhang,Shuang Guan
Capsaicin (CAP), the active ingredient in hot chilli peppers, has anti-inflammatory and hepatoprotection effects. Acute alcoholic liver injury (AALI) is liver damage caused by acute alcohol abuse, which can lead to severe liver lesions and even be life-threatening. Pyroptosis is inflammation-related programmed cell death characterized by membrane rupture and plays a key role in AALI. The endosomal sorting complexes required for transport (ESCRT) proteins can gather at damaged areas of the membrane to facilitate the process of sealing the membrane. In this study, we found that CAP could relieve acute alcohol-induced pyroptosis of hepatocytes in vitro and in vivo. Mechanically, we found that CAP could alleviate acute alcohol-induced pyroptosis by activating the ESCRT-III-dependent membrane repair machinery. Furthermore, the data showed that CAP induced ESCRT-III protein expression by activating transient receptor potential vanilloid member 1 (TRPV1) on the cell membrane and Ca2+ influx. TRPV1 inhibitor capsazepine (CPZ) inhibited the relief effect of CAP on acute alcohol-induced pyroptosis. Overall, these results showed that CAP might activate ESCRT-III-dependent membrane repair machinery through Ca2+ influx, which is regulated by TRPV1 calcium channels, therefore mitigating acute alcohol-induced pyroptosis. Our research provides a new perspective on a naturally active food product to promote cell repair and relieve AALI.
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Materials Today
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2025
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IF 22
Ying-Tao Zhong,Zi-Wen Qiu,Ke-Yan Zhang,Zhen-Ming Lu,Zhuo-Feng Li,Jun-Mei Nie,Yi Cen,Hong Cheng,Shi-Ying Li,Xiaoyuan Chen
Pyroptosis-inducing chemotherapeutics hold promise for activating both adaptive and innate immunity in breast cancer immunotherapy. However, their practical efficacy is often limited by inadequate expression of pyroptosis-executed gasdermin and insufficient transfer of tumor-derived DNA. In this work, our findings indicated that the epigenetic drug of decitabine (DEC) can increase the gasdermin E (GSDME) level in breast cancer cells, while the DNA-damaging chemotherapeutic drug of 7-ethyl-10-hydroxycamptothecin (SN38) can activate caspase-3 and cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) pathway. Based on these discoveries, a glutathione (GSH)-responsive nanoplatform equipped with PD-L1 blockade peptide (PD-L1 pep) is further fabricated for targeting delivery of these chemotherapeutic combination to breast cancer cells. Interestingly, the apoptosis-pyroptosis switch (denoted as PL@SD) not only enables the cascade activation of caspase-3 and GSDME to induce an apoptosis-pyroptosis transition, but also accelerates the release of tumor-derived DNA through the pore-formation to elicit the cGAS-STING activity. Concurrently, PL@SD elevates dendritic cell maturation, cytotoxic T lymphocyte infiltration, natural killer cell recruitment and long-term immunological memory effect to boost adaptive and innate immunity, thus synergistically suppressing primary breast cancer, distant lung metastases and tumor rechallenge. Overall, this study presents an elaborate strategy for apoptosis-pyroptosis transition and cGAS-STING activation, which might provide a new insight to expand the applications of the existing therapeutic drugs for tumor immunotherapy.
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Journal of Advanced Research
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2024
·
IF 11.4
Jun Ma,Peng Yang,Zhibin Zhou,Tengfei Song,Liang Jia,Xiaofei Ye,Wei Yan,Jiuyi Sun,Tianwen Ye,Lei Zhu
Introduction Osteoarthritis (OA) is the most common arthritis that is characterized by the progressive synovial inflammation and loss of articular cartilage. Although GYY4137 is a novel and slow-releasing hydrogen sulfide (H 2 S) donor with potent anti-inflammatory properties that may modulate the progression of OA, its underlying mechanism remains unclear. Objectives In this study, we validated the protective role of GYY4137 against OA pathological courses and elucidated its underlying regulatory mechanisms. Methods Cell transfection, immunofluorescence staining, EdU assay, transmission electron microscopy, mitochondrial membrane potential measurement, electrophoretic mobility shift assay, sulfhydration assay, qPCR and western blot assays were performed in the primary mouse chondrocytes or the mouse macrophage cell line raw 264.7 for in vitro study. DMM-induced OA mice model and Macrophage-specific p65 knockout (p65 f/f LysM-CreER T2 ) mice on the C57BL/6 background were used for in vivo study. Results We found that GYY4137 can alleviate OA progress by suppressing synovium pyroptosis in vivo. Moreover, our in vitro data revealed that GYY4137 attenuates inflammation-induced NLRP3 and caspase-1 activation and results in a decrease of IL-1β production in macrophages. Mechanistically, GYY4137 increased persulfidation of NF-kB p65 in response to inflammatory stimuli that results in a decrease of cellular reactive oxygen species (ROS) accumulation and ameliorates mitochondrial dysfunctions. Using site-directed mutagenesis, we showed that H 2 S persulfidates cysteine38 in p65 protein and hampers p65 transcriptional activity, and p65 mutant impaired macrophage responses to GYY4137. Conclusion These findings suggest a mechanism by which GYY4137 through redox modification of p65 participates in inhibiting NLRP3 activation by OA to regulate inflammatory responses. Thus, we propose that GYY4137 represents a promising novel therapeutic strategy for the treatment of OA.
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Theranostics
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2024
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IF 12.4
Jing Ye,Xinyuan Bi,Shiyu Deng,Xianghui Wang,Ze Liu,Qian Suo,Jiao Wu,Haoran Chen,Yong Wang,Kun Qian,Rubing Shi,Jing Zhao,Guo-Yuan Yang,Jian Ye,Yaohui Tang
Rationale: Stroke induces metabolic changes in the body, and metabolites have become potential biomarkers for stroke. However, the specific metabolites involved in stroke and the mechanisms underlying brain injury during stroke remain unclear. Methods: Surface-enhanced Raman spectroscopy (SERS) and liquid chromatography-mass spectrometry (LC‒MS) analysis of clinical serum samples from 69 controls and 51 ischemic stroke patients who underwent reperfusion within 24 hours were performed to identify differentially abundant metabolites. Mice were subjected to transient middle cerebral artery occlusion (tMCAO) and then intravenously injected with hypoxanthine. The infarct area was evaluated via tetrazolium chloride (TTC) staining, and behavior tests were conducted. Blood-brain barrier (BBB) leakage was assessed by Evans blue and IgG staining. Human blood vessel organoids were used to investigate the mechanism of hypoxanthine-induced pyroptosis of endothelial cells. Results: SERS and LC‒MS revealed the metabolic profiles of serum from stroke patients and controls with high sensitivity, speed and accuracy. Hypoxanthine levels were significantly elevated in the acute stage of ischemic stroke in both patients and mice (p < 0.001 after Bonferroni correction). In addition, increasing hypoxanthine increased the infarct area and aggravated BBB leakage and neurobehavioral deficits in mice after ischemic stroke. Further mechanistic studies using endothelial cells, human blood vessel organoids, and stroke mice demonstrated that hypoxanthine-mediated gasdermin E (GSDME)-dependent pyroptosis of endothelial cells occurs through intracellular Ca 2+ overload. Conclusion: Our study identified hypoxanthine as an important metabolite that induces vascular injury and BBB disruption in stroke through triggering GSDME-dependent pyroptosis of endothelial cells.
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BIOMEDICINE & PHARMACOTHERAPY
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2024
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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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