INTERNATIONAL IMMUNOPHARMACOLOGY
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2026
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IF 5.6
Jian Yu,Jiangtao Wang,Ning Feng,Cancan Wang,Bohua Ma,Yuanming Zhang
Background Among the adverse effects of immunotherapy in cancer patients, immune checkpoint inhibitors (ICIs)-induced myocarditis is the most severe. Pyroptosis is involved in the pathogenesis of various cardiovascular diseases; however, its relationship with ICIs-related myocarditis remains unclear. Objective The purpose of this research is to characterize the critical genes mediating pyroptosis in myocarditis related to ICIs, with the goal of informing clinical practice. Materials and methods Based on single-cell RNA sequencing and bulk RNA sequencing, this study identified pyroptosis key genes in ICIs-related myocarditis and validated their expression levels and diagnostic value. Single-cell level validation of key genes, trajectory analysis and cellular interactions were also performed. Finally, ICIs-related myocarditis mouse model was established to verify the expression levels of key genes and pyroptosis-related markers. Results Integration of multiple bioinformatic analyses identified two pyroptosis key genes in ICIs-related myocarditis: Myd88 and Sqstm1. The expression levels of pyroptosis key genes were significantly higher in the ICIs-related myocarditis group compared to the normal group ( P < 0.05 or P < 0.01), and both demonstrated high diagnostic value. Trajectory analysis and cell interaction analysis revealed the interaction strength and relative expression patterns between these two pyroptosis key genes. In the ICIs-related myocarditis mouse model, cardiac injury markers were significantly elevated ( P < 0.001 or P < 0.0001), while cardiac function indices were significantly decreased ( P < 0.01) compared to the normal group. Quantitative real time polymerase chain reaction and western blot analyses revealed that the expression levels of Myd88 and Sqstm1 were significantly upregulated in the myocarditis group compared to the normal group, at both the mRNA and protein expression levels ( P < 0.05 or P < 0.01 or P < 0.0001). Compared with the normal group, the expression levels of pyroptosis-related markers Caspase-1, IL-1β, and GSDMD-N were significantly elevated in the myocarditis group ( P < 0.05 or P < 0.01). Conclusion Pyroptosis is involved in the pathogenesis of ICIs-related myocarditis, and Myd88 and Sqstm1 may serve as potential biomarkers for future clinical application.
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Pharmacognosy Magazine
·
2025
·
IF 0.9
Qing Liu,Ying Lan,Zhe Bai
BackgroundHyperoside is a potential liver cell and mitochondrial protector, but there is no evidence to suggest that hyperoside can effectively treat doxorubicin (DOX) related liver toxicity.PurposeThis study aims to determine the role of hyperoside in DOX related liver toxicity and liver cell damage in vivo and in vitro.MethodsA mouse model of liver toxicity was induced by intraperitoneal injection of DOX, and hyperoside was administered orally for treatment. During this period, the weight and food intake of the mice were recorded. The morphology of mouse liver tissue was observed by hematoxylin and eosin staining. Oxidative stress and inflammatory status in mice were observed through serum inflammatory factors and liver oxidative stress markers. Mitochondrial damage is determined by the degree of mitochondrial DNA damage. Western blotting and reverse transcription polymerase chain reaction (RT-PCR) were used to detect the expression of pyroptosis and genes in the liver and liver cells.ResultsHyperoside can effectively treat DOX-induced oxidative stress and inflammatory status, liver function damage, and hepatocyte necrosis in mice. Further research suggests that the beneficial effect of hyperoside is achieved by inhibiting mitochondrial DNA damage in liver cells.ConclusionThis study indicates that hyperoside improves DOX-induced liver toxicity by inhibiting mitochondrial DNA damage.
研究领域:
药理学
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肝脏病学
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分子生物学
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MOLECULAR AND CELLULAR BIOCHEMISTRY
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2021
·Vol. 476
·期 6
·2479-2489
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IF 3.396
Chai Qian,Meng Ziang,Lu Dexue,Zhang Ziying,Liu Meili,Wu Weihua
Cardiomyocyte death is an important pathogenic process in cardiac complications of diabetes. Diabetic patients often suffer glycemic variability. Pyroptosis is a form of programmed cell death triggered by inflammasomes and related with caspase-1 and gasdermin D activation. The present study was designed to examine the effects of intermittent high glucose simulating glycemic variability on the pyroptosis of cardiomyocytes in vitro. Rat H9C2 cardiomyocytes were incubated with normal glucose (NG), constant high glucose (CHG) and intermittent high glucose (IHG). Results showed that compared to CHG treatment, IHG further inhibited cell proliferation and promoted cell death of H9C2 cardiomyocytes. In addition, IHG upregulated higher levels of the expressions of inflammasome NLR family pyrin domain containing 3 (NLRP3) and adaptor protein apoptosis-associated speck-like protein containing CARD domain (ASC) and increased higher levels of activated caspase-1 and gasdermin D than CHG treatment. Moreover, the production of reactive oxygen species (ROS) and activation of NF-κB that is induced by IHG were significantly higher than that induced by CHG. Knockdown of sodium–glucose cotransporters 1 (SGLT1) in H9C2 cardiomyocytes was performed and the effects of SGLT1 on IHG-induced pyroptosis was evaluated. The results demonstrated that knockdown of SGLT1 partially reduced IHG-induced pyroptosis, ROS generation and NF-κB activation. Our results indicated that IHG is harmful to cardiomyocytes and it might be partially because of the SGLT1-depedent pyroptosis in cardiomyocytes.
研究领域:
心脏病学
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糖尿病
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细胞生物学
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分子生物学
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Small
·
2022
·Vol. 19
·期 9
·2205531
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IF 15.153
Qian-Wei Luo,Lu Yao,Ling Li,Zhuo Yang,Mei-Mei Zhao,Yong-Zhe Zheng,Fang-Fang Zhuo,Ting-Ting Liu,Xiao-Wen Zhang,Dan Liu,Peng-Fei Tu,Ke-Wu Zeng
Understanding the direct interaction of nanostructures per se with biological systems is important for biomedical applications. However, whether nanostructures regulate biological systems by targeting specific cellular proteins remains largely unknown. In the present work, self-assembling nanomicelles are constructed using small-molecule oleanolic acid (OA) as a molecular template. Unexpectedly, without modifications by functional ligands, OA nanomicelles significantly activate cellular proteasome function by directly binding to 20S proteasome subunit alpha 6 (PSMA6). Mechanism study reveals that OA nanomicelles interact with PSMA6 to dynamically modulate its N-terminal domain conformation change, thereby controlling the entry of proteins into 20S proteasome. Subsequently, OA nanomicelles accelerate the degradation of several crucial proteins, thus potently driving cancer cell pyroptosis. For translational medicine, OA nanomicelles exhibit a significant anticancer potential in tumor-bearing mouse models and stimulate immune cell infiltration. Collectively, this proof-of-concept study advances the mechanical understanding of nanostructure-guided biological effects via their inherent capacity to activate proteasome.
研究领域:
纳米技术
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癌症生物学
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分子生物学
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生物医学工程
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PeerJ
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2023
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IF 2.7
Linlin Sun,Miao Ding,Fuhua Chen,Dingyu Zhu,Xinmiao Xie
Podocyte injury is a critical factor in the pathogenesis of diabeticnephropathy (DN). Emerging evidence has demonstrated that breviscapine (Bre) exerts a renoprotective effect on diabetic rats. However, the effects of Bre on regulating podocyte injury under high glucose (HG) conditions remain unclear. In this study, an experimental mouse model of DN was induced by intraperitoneal injections of streptozotocin (STZ) in vivo . The effects of Bre on podocyte injury were assessed using cell counting kit-8 (CCK-8) assay, TdT-mediated dUTPnick-endlabelling (TUNEL) staining, quantitative real-time PCR (qRT‒PCR) and western blot analysis. We found that renal function was significantly decreased in diabetic mice, and this effect was blocked by Bre treatment. Bre effectively increased podocyte viability and inhibited HG-induced cell apoptosis. Furthermore, Bre ameliorated HG-induced podocyte injury, as evidenced by decreased α-smooth muscle actin (α-SMA) expression and increased podocin and synaptopodin expression. Mechanistically, Bre inhibited HG-induced nuclear factorkappaB (NF-κB) signalling activation and subsequently decreased NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, resulting in a decrease in pyroptosis. Pharmacological inhibition of NLRP3 decreased HG-induced podocyte injury, whereas the NLRP3 agonist abrogated the effects of Bre on inhibiting podocyte injury. In summary, these results demonstrate that Bre alleviates HG-induced podocyte injury and improves renal function in diabetic mice, at least in part by inhibiting NF-κB/NLRP3-mediated pyroptosis.
研究领域:
药理学
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肾病学
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分子生物学
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IMMUNITY
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2023
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IF 32.4
Xia Chen,Rong Wu,Lei Li,Yunong Zeng,Jingrui Chen,Mingyuan Wei,Yinglin Feng,Guiming Chen,Yuhang Wang,Lizhen Lin,Haihua Luo,Ali Chen,Zhenhua Zeng,Fangjie He,Yang Bai,Siyou Zhang,Yubing Han,Zhang Wang,Xiaoshan Zhao,Wei Xiao,Yong Jiang,Shenhai Gong
The physiological and immune changes that occur during pregnancy are associated with worsened disease outcomes during infection and sepsis. How these perturbations exacerbate inflammation has not been explored. Here, using antibiotic treatment and fecal microbial transfers, we showed that sepsis susceptibility is driven by pregnancy-induced changes to gut microbiome in mice and humans. Integrative multiomics and genetically engineered bacteria revealed that reduced Parabacteroides merdae ( P. merdae ) abundance during pregnancy led to decreased formononetin (FMN) and increased macrophage death. Mechanistically, FMN inhibited macrophage pyroptosis by suppressing nuclear accumulation of hnRNPUL2 and subsequent binding to the Nlrp3 promoter. Treatment with FMN or deletion of murine hnRNPUL2 protected against septic inflammation. Intestinal abundances of P. merdae and FMN inversely correlated with the progression of septic patients. Our data reveal a microbe-immune axis that is disrupted in pregnant septic hosts, highlighting the potential of the FMN-hnRNPUL2-NLRP3 axis in providing promising therapeutic strategies for sepsis.
研究领域:
免疫学
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微生物学
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传染病学
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ENVIRONMENTAL TOXICOLOGY
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2023
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IF 4.5
Zhihui Li,Yan Shi,Yougang Wang,Haomin Qi,Haiyu Chen,Jinquan Li,Li Li
Cadmium (Cd) is a hypertoxic heavy metal that may be exposed to environmental pollutants by humans and animals. It can lead to cognitive disfunction, and is linked to neurodegenerative diseases. Cadmium reportedly can induce endoplasmic reticulum (ER) stress, but few studies have concentrated on it in nerve cells, and the connection between ER stress and neuroinflammation. In this study, in vitro experiments on SH-SY5Y neuroblastoma cells were carried out. We aimed at exploring whether Cd attributed to the cell pyroptosis and the role of PERK in promoting this form of cell damage which can induce strong inflammatory responses. Our results demonstrated that CdCl 2 treatment induced excess reactive oxygen species (ROS) production, caused significant modifications in the expression of PERK and increased TXNIP, NLRP3, IL-1β, IL-18, and caspase1 in SH-SY5Y cells. In addition, scavenging ROS with N -acetylcysteine or inhibiting the expression of PERK by using GSK2606414, rescued the SH-SY5Y cells from cadmium-induced pyroptosis. In conclusion, the results suggest that Cd induces pyroptotic death of SH-SY5Y cells through ER stress, and this may be the potential mechanism of Cd incurring neurological diseases.
研究领域:
神经毒理学
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细胞生物学
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分子生物学
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环境毒理学
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MOLECULAR NEUROBIOLOGY
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2022
·Vol. 59
·期 11
·6934-6955
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IF 5.682
Wu Yueshan,Chang Jing,Ge Juanjuan,Xu Kangyan,Zhou Quan,Zhang Xiaowen,Zhu Ni,Hu Meichun
Glioblastoma multiforme (GBM) is the most malignant intracranial tumor with high mortality rates and invariably poor prognosis due to its limited clinical treatments. There is an urgent need to develop new therapeutic drugs for GBM treatment. As a natural prenylated chalcone compound, Isobavachalcone (IBC)’s favorable pharmacological activities have been widely revealed. However, potential inhibitory effects of IBC on GBM have not been explored. In the present study, we aimed to detect the effects of IBC on GBM and clarify its anti-GBM mechanisms for the first time. It was observed that IBC could inhibit GBM cell proliferation, migration, and invasion in vitro and prevent tumor growth without any significant drug toxicity in both subcutaneous and orthotopic GBM xenograft tumor models in vivo. Mechanistically, IBC may target NOD-like receptor family pyrin domain-containing 3 (NLRP3) transcription factor estrogen receptor α ( ESR1 gene) by network pharmacology and molecular docking analysis. Experimentally, IBC alleviated NLRP3 inflammasome-related pyroptosis and inflammation, arrested cell cycle at G1 phase, and induced mitochondria-dependent apoptosis in GBM cells. IBC’s inhibition on NLRP3 could be rescued by the NLRP3 antagonist CY-09 both in vitro and in vivo. These results indicate that IBC is a potential therapeutic drug against GBM and provide a new insight into GBM treatment.
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
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Drug Design Development and Therapy
·
2022
·
IF 4.319
Bozhi Ye,Xudong Chen,Shanshan Dai,Jibo Han,Xiaohe Liang,Shuang Lin,Xueli Cai,Zhouqing Huang,Weijian Huang
Background Emodin has recently been reported to have a powerful antiinflammatory effect, protecting the myocardium against ischemia/reperfusion (I/R) injury. Pyroptosis is a proinflammatory programmed cell death that is related to many diseases. The present study investigated the effect of emodin on pyroptosis in cardiomyocytes.Materials and methods Sprague Dawley rats were randomly divided into sham, I/R, and I/R+Emodin groups. I/R model was subjected to 30 minutes’ ligation of left anterior descending coronary artery, followed by 2 hours of reperfusion. Cardiomyocytes were exposed to hypoxic conditions for 1 hour and normoxic conditions for 2 hours. The level of the pyroptosis was detected by Western blot, real-time PCR analysis, and ELISA.Results The level of gasdermin D-N domains was upregulated in cardiomyocytes during I/R or hypoxia/reoxygenation (H/R) treatment. Moreover, emodin increased the rate of cell survival in vitro and decreased the myocardial infarct size in vivo via suppressing the levels of I/R-induced pyroptosis. Additionally, the expression of TLR4, MyD88, phospho-IκBα, phospho-NF-κB, and the NLRP3 inflammasome was significantly upregulated in cardiomyocytes subjected to H/R treatment, while emodin suppressed the expression of these proteins.Conclusion This study confirms that emodin treatment was able to alleviate myocardial I/R injury and inhibit pyroptosis in vivo and in vitro. The inhibitory effect of emodin on pyroptosis was mediated by suppressing the TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway. Therefore, emodin may provide an alternative treatment for myocardial I/R injury.
研究领域:
药理学
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心脏病学
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细胞生物学
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分子生物学
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Materials Today Bio
·
2023
·
IF 8.2
Boshu Ouyang,Lingling Deng,Fangyong Yang,Hanlin Shi,Na Wang,Weifeng Tang,Xi Huang,Yaolong Zhou,Hang Yu,Ying Wei,Jingcheng Dong
Pulmonary fibrosis that occurs following lung injury is a progressive and fatal disease since continual damage to lung tissue triggers the dysregulated inflammation response and accompanying abnormal healing process. Pyroptosis of alveolar macrophages has been found to play an essential role in the deterioration of lung injury and fibrosis. However, the lack of inhibitors against this inflammatory cell death in macrophages and the dense stroma pose major barriers to lung injury and fibrosis treatment. Herein, we developed an albumin-based nanoformulation to realize active delivery of formononetin (FMN) to improve the treatment of lung injury and fibrosis. The obtained nanoparticle, [email protected] NPs, could efficiently accumulate at the impaired lesion benefiting from the leaky vasculatures and the affinity between albumin and the overexpressed SPARC protein. Through blocking the NLRP3 inflammasome-involved pyroptosis process of macrophages, [email protected] NPs remarkably improved lung function and prolonged animal survival in the bleomycin (BLM)-induced lung injury and fibrosis model without noticeable side effects. Meanwhile, we proved FMN as a pyroptosis inhibitor and the corresponding lipid metabolism-related mechanisms through multi-omics analysis. This study first employed an albumin-based nanoparticle to deliver the pyroptosis inhibitor to the impaired lung tissue actively, providing a promising strategy for lung injury and fibrosis treatment.
研究领域:
药学
·
肺科学
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纳米技术
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炎症生物学
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Advanced Science
·
2023
·
IF 15.1
Liang Xiao,Benjin Chen,Wanni Wang,Tian Tian,Haisheng Qian,Xiaohu Li,Yongqiang Yu
Radiotherapy (RT), a widely used clinical treatment modality for cancer, uses high-energy irradiation for reactive oxygen species (ROS) production and DNA damage. However, its therapeutic effect is primarily limited owing to insufficient DNA damage to tumors and harmful effects on normal tissues. Herein, a core-shell structure of metal–semiconductors (Au@AgBiS 2 nanoparticles) that can function as pyroptosis inducers to both kill cancer cells directly and trigger a robust anti-tumor immune against 4T1 triple-negative murine breast cancer and metastasis is rationally designed. Metal-semiconductor composites can enhance the generation of considerable ROS and simultaneously DNA damage for RT sensitization. Moreover, Au@AgBiS 2 , a pyroptosis inducer, induces caspase-3 protein activation, gasdermin E cleavage, and the release of damage-associated molecular patterns. In vivo studies in BALB/c mice reveal that Au@AgBiS 2 nanoparticles combined with RT exhibit remarkable antitumor immune activity, preventing tumor growth, and lung metastasis. Therefore, this core-shell structure is an alternative for designing highly effective radiosensitizers for radioimmunotherapy.
研究领域:
纳米技术
·
肿瘤学
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免疫治疗
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放射生物学
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高影响因子
TISSUE & CELL
·
2025
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IF 2.5
Minhui Wang,Daojun Chen,Daofa Zhang,Hui Han,Maowei Xie,Ying Zhang,Yun Cao,Jiali Wei
Background Renal fibrosis (RF) is a common histopathological feature of chronic kidney disease (CKD) and is closely associated with persistent inflammation and regulated cell death. However, the underlying molecular mechanisms of pyroptosis in RF are unclear. Methods Pyroptosis-related hub genes in RF were identified through bioinformatics analysis. Granzyme B ( GZMB ) was knocked down in transforming growth factor (TGF-β)-stimulated HK-2 cells and in a folic acid (FA)-induced nephropathy mouse model. Western blot and enzyme-linked immunosorbent assays were performed to detect the expression of fibrosis and pyroptosis-related markers. Cell viability was assessed by the Cell Counting Kit-8 assay. Hematoxylin and eosin (HE) and Masson's staining were used to evaluate tubular injury and collagen deposition in renal tissues. Results GZMB was identified as a pyroptosis-associated hub gene. It was significantly upregulated in RF and exhibited high diagnostic performance. In TGF-β-stimulated HK-2 cells, GZMB knockdown enhanced cell viability and reduced lactate dehydrogenase release. In vivo , GZMB silencing ameliorated tubular injury, reduced collagen deposition, and improved renal function. The expression levels of pyroptosis-related proteins, including the N-terminal fragment of gasdermin D, cleaved caspase-1, and NOD-like receptor family pyrin domain containing 3 (NLRP3), as well as fibrotic markers alpha-smooth muscle actin and collagen type I, were downregulated after GZMB knockdown. Mechanically, GZMB knockdown inhibited NLRP3 inflammasome activation and suppressed the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway. Conclusion GZMB deficiency inhibits pyroptosis and dampens the JAK2/STAT3 pathway, representing a potential approach for RF treatment.
研究领域:
肾脏病学
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分子生物学
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细胞信号传导
·
炎症
·
纤维化研究
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PubMed
高影响因子
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