JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY
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2024
·Vol. 75
·期 3
·
IF 2
Q Y Zhang,Y Feng,H Cai
Bronchopulmonary dysplasia (BPD) is a common serious complication of premature babies. No effective means control it. Hyperoxia damage is one of the important mechanisms of BPD. The reaserach confirmed pyroptosis existed in BPD. Dexmedetomidine is a new, high-specific α2 receptor agonist. Previous research foundation found that dexmedetomidine has a protective effect on BPD. To investigate how dexmedetomidine improves hyperoxic lung injury in neonatal mice by regulating pyroptosis. Neonatal rats were randomly divided into four groups: normal control group, hyperoxic injury group, air plus dexmedetomidine group, and hyperoxia plus dexmedetomidine group. After seven days the lungs of rats in each group were extracted, and the wet-to-dry weight ratio of the lung was measured. The lung injury in rats was observed using hematoxylin-eosin staining. Additionally, the expression and localization of nucleotide-binding oligomerization domain-like receptor thermal protein domain associated protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), and gasdermin D (GSDMD) proteins were examined in the lungs of rats using immunofluorescence staining. The mRNA levels of NLRP3, ASC, caspase-1, and interleukin 18 (IL-18) in the lungs of rats were determined using real-time PCR. Moreover, the protein levels of NLRP3, ASC, caspase-1/cleaved caspase-1, interleukin 1beta (IL-1β), IL-18, and tunor necrosis factor alpha (TNF-α) were detected in lungs of rats using Western blot. The extent of mitochondrial damage in lung tissues of each group was observed by transmission electron microscopy. The lung tissue injury of the neonatal rats was significantly improved in the hyperoxia plus dexmedetomidine group compared to the hyperoxic injury group. Furthermore, the expressions of pyroptosis-related proteins such as NLRP3, ASC, cleaved-caspase-1, and GSDMD were significantly decreased, along with the expressions of inflammatory factors in lung tissues. By inhibiting the NLRP3/caspase-1/GSDMD pyroptosis pathway, dexmedetomidine reduces the activation and release of inflammatory factors and provides a protective effect against hyperoxic lung injury in neonatal mice.
研究领域:
儿科
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呼吸医学
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药理学
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分子生物学
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免疫学
✓ 已验证
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF CELL BIOLOGY
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2021
·
IF 4.492
Jian Zhao,Zhaoyu Liu,Zhihui Chang
Endothelial cell pyroptosis is a novel cause of endothelial dysfunction in sepsis. Reticulocalbin-2 (RCN2) is involved in regulating vascular inflammation and plays an important role in the cardiovascular system. However, the role of RCN2 in inflammation-induced endothelial cell pyroptosis remains to be explored. Here, we found that RCN2 was upregulated after lipopolysaccharide (LPS) treatment in a concentration‐ and time-dependent manner. RCN2 knockdown resulted in a significant decrease in pyroptosis, reduced LDH and IL-1β release and ROS production and inhibited the expression of pyroptosis‐related proteins (NLRP3, cleaved caspase-1, and cleaved GSDMD) (all p < 0.05). N‐acetyl‐L‐cysteine (NAC) counteracted the effects of RCN2 on pyroptosis (all p < 0.01). The silencing of RCN2 antagonized the inhibitory effect of LPS on the phosphorylation of eNOS (p < 0.05). We predicted and confirmed that specificity protein-1(SP1) could directly bind to the RCN2 promoter and regulate RCN2. RCN2 overexpression rescued the inhibitory effect of SP1 inhibitor on HUVEC pyroptosis induced by LPS (all p < 0.05). These findings suggested that the activation of the SP1/RCN2/ROS signaling pathway could promote LPS-induced endothelial cell pyroptosis.
研究领域:
免疫学
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心血管生物学
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细胞信号传导
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炎症
✓ 已验证
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2023
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IF 11.2
E Zhang,Chuangeng Shang,Mingtao Ma,Xuanfeng Zhang,Yu Liu,Shuliang Song,Xia Li
Polyguluronic acid (PG), a polysaccharide from alginate , possesses excellent bioactivities. We prepared high-purity PG with 10.41 kDa molecular weight (Mw) and a 59 average degree of polymerization (DP) by acid hydrolysis , three pH grades, Q-Sepharose column elution, and Sephadex G-25 column desalination . Then, we evaluated the PG protective effects on doxorubicin-induced cardiotoxicity (DIC) in vitro and in vivo. The nontoxic PG enhanced cellular viability , reduced cell pyroptosis morphology, diminished the LDH and IL-1β release, and downregulated expressions of ASC oligomerization , NLRP3 , cl-CASP1, and GSDMD, by which PG protected the cardiomyocytes from NLRP3 inflammasome-mediated pyroptosis in doxorubicin-stimulated HL-1 cells and C57BL/6J mice. The probable underlying mechanism may be that PG downregulated doxorubicin -induced Peli1, the deficiency of which could inhibit doxorubicin-induced NLRP3 inflammasome-mediated pyroptosis. These results suggested that polysaccharide PG from alginate could prevent DIC and may be a potential therapeutic agent or bioactive material for preventing DIC.
研究领域:
药理学
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心脏病学
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免疫学
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生物化学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
·
IF 6.2
Jinzhao Zhou,Yanwei Zhang,Ling Zeng,Xiaofei Wang,Wenpei Xiang,Ping Su
Cadmium (Cd) is a harmful metal that seriously affects the male reproductive system, but the mechanism of how Cd exposure damages Sertoli cells is not fully understood. This study used TM4 cells to explore the mechanism of Cd damage to Sertoli cells. We found that Cd was concentration- and time-dependent on TM4 cell viability. Cd exposure increased intracellular reactive oxygen species (ROS) levels, lactate dehydrogenase (LDH), and Interleukin-1β (IL-1β) release in TM4 cells, decreased mitochondrial function, and increased pyroptosis. N-acetylcysteine (NAC), MCC950 and BAY 11–7082 (BAY) alleviate the release of IL-1β and LDH induced by Cd. NAC reduced Cd induced increases in ROS, NLRP3, Caspase-1, Heme oxygenase-1(HO-1), superoxide dismutase (SOD2), and increased mitochondrial function. The activation of GSDMD is the main causes of pyroptosis, and NAC significantly inhibit its activation and formation. Our results suggest that Cd exposure induces a toxic mechanism of GSDMD-mediated pyroptosis in TM4 cells by increasing ROS levels and activating the inflammasome.
研究领域:
毒理学
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细胞生物学
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生殖健康
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DNA AND CELL BIOLOGY
·
2022
·Vol. 41
·期 12
·1038-1052
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IF 3.55
Qianyu Tang,Wenhui Liu,Xuefeng Yang,Yaying Tian,Jiacheng Chen,Yang Hu,Nian Fu
Despite activated autophagy ameliorating hepatocyte steatosis and metabolic associated fatty liver disease (MAFLD), mechanisms underlying the beneficial roles of autophagy in hepatic deregulation of lipid metabolism remain undefined. We explored whether autophagy can ameliorate oleic acid (OA)-induced hepatic steatosis by suppressing pyroptosis. Pyroptosis is involved in hepatocyte steatosis induced by OA. In addition, autophagy flux was blocked in OA-treated hepatocytes. Treatment with OA induced lipid accumulation in liver cell line L-02, which was attenuated by rapamycin (Rap), an autophagy agonist, while aggravated by autophagy inhibitor bafilomycin A1 (Baf A1). Inversely, treatment with pyroptotic agonist Nigericin aggravated OA-induced hepatic steatosis, while pyroptosis antagonist disulfiram ameliorated this effect. Mechanistically, treatment with Rap downregulated the expression of pyroptosis-related proteins, including NLRP3, Caspase-1, IL-18, GSDMD expression evoked by OA, thus improving pyroptosis in hepatic steatosis. Significantly, overexpression of ATG5 obviously downregulated cleaved caspase-1 expressions without altering the total caspase1 expressions in hepatic cell steatosis. Taken together, our studies strongly demonstrated that the activation of ATG5 inhibits pyroptosis to improve hepatic steatosis and suggest autophagy activation as a potential therapeutic strategy for pyroptosis-mediated MAFLD.
研究领域:
肝脏病学
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细胞生物学
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分子生物学
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药理学
✓ 已验证
DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2018
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IF 3.432
Xiaomin Xia,Bin Lu,Wenjing Dong,Bingwei Yang,Yawen Wang,Qi Qin,Zixuan Liu,Erqun Song,Yang Song
Our previous study showed that tetrachlorobenzoquinone (TCBQ) mediated the activation of Nod-like receptor protein 3 (NLRP3) inflammasome, which involves K+ efflux, reactive oxygen species (ROS) production, and mitochondrial DNA damage. In addition, TCBQ down-regulates NLRP3 ubiquitination and promotes the activation of NLRP3 inflammasome. However, the induction of NLRP3 inflammasome by atypical pathways has not yet been characterized. Using human umbilical vein endothelial cells (HUVEC), we discovered that TCBQ activates caspase 1/4/5 and cleaves gasdermin D (GSDMD) into N-terminal and C-terminal cleavage products. In parallel, TCBQ also activates receptor interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like protein (MLKL) signaling pathways. The N-terminal fragments of GSDMD and MLKL translocate from cytoplasm to cell membrane and form oligomers and membrane pores on the cell membrane. The formation of membrane pores not only promotes the extracellular secretion of interleukin 1 beta (IL-1β) but also affects cellular ion homeostasis, in particular promotes K+ outflow, which further activates NLRP3 inflammasome and aggravates cellular inflammation. These results indicated that GSDMD and MLKL play important roles in TCBQ-induced endothelial pro-inflammatory responses, which may point to potential therapeutic approaches for TCBQ-mediated toxicity.
研究领域:
毒理学
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免疫学
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细胞生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Yuan Xu,Xin An,Lei Liu,Xinran Cao,Zhanfeng Wu,Wang Jia,Jiacheng Sun,Haoyu Wang,Jiawei Huo,Zihao Sun,Mingming Zhen,Chunru Wang,Chunli Bai
Endotoxemia is a life-threatening multiple organ failure disease caused by bacterial endotoxin infection. Unfortunately, current single-target therapy strategies have failed to prevent the progression of endotoxemia. Here, we reported that alanine fullerene redox modulator (AFRM) remodeled the intestinal microenvironment for multiple targets endotoxemia mitigation by suppressing inflammatory macrophages, inhibiting macrophage pyroptosis, and repairing epithelial cell barrier integrity. Specifically, AFRM exhibited broad-spectrum and self-cascade redox regulation properties with superoxide dismutase (SOD)-like enzyme, peroxidase (POD)-like enzyme activity, and hydroxyl radical (•OH) scavenging ability. Guided by proteomics, we demonstrated that AFRM regulated macrophage redox homeostasis and down-regulated LPS/TLR4/NF-κB and MAPK/ERK signaling pathways to suppress inflammatory hyperactivation. Of note, AFRM could attenuate inflammation-induced macrophage pyroptosis via inhibiting the activation of gasdermin D (GSDMD). In addition, our results revealed that AFRM could restore extracellular matrix and cell-tight junction proteins and protect the epithelial cell barrier integrity by regulating extracellular redox homeostasis. Consequently, AFRM inhibited systemic inflammation and potentiated intestinal epithelial barrier damage repair during endotoxemia in mice. Together, our work suggested that fullerene based self-cascade redox modulator has the potential in the management of endotoxemia through synergistically remodeling the inflammation and epithelial barriers in the intestinal microenvironment.
研究领域:
药理学
·
免疫学
·
病理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2022
·
IF 7.129
Yi Zhang,Bo Hu,Xiaolan Qian,Guangtao Xu,Xin Jin,Deqing Chen,Jie Tang,Long Xu
Environmental pollution often releases multiple contaminants resulting in as yet largely uncharacterized additive toxicities. Cadmium (Cd) is a widespread pollutant that induces nephrotoxicity in animal models and humans. However, the combined effect of Cd in causing nephrotoxicity with 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), a typical congener of polybrominated diphenyl ethers (PBDEs), has not been evaluated and mechanisms are not completely clear. Here, we applied transcriptome sequencing analysis to investigate the combined toxicity of Cd and BDE-47 in the renal tubular epithelial cell lines HKCs. Cd or BDE-47 exposure decreased cell viability in a dose-dependent manner, and exhibited cell swelling and rounding similar to necrosis, which was exacerbated by co-exposure. Transcriptomic analysis revealed 2191, 1331 and 3787 differentially-expressed genes following treatment with Cd, BDE-47 and co-exposure, respectively. Interestingly, functional annotation and enrichment analyses showed involvement of pathways for oxidative stress, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and inflammatory cell death for all three treatments. Examination of indices of mitochondrial function and oxidative stress in HKC cells showed that the levels of reactive oxygen species (ROS), malondialdehyde (MDA) and intracellular calcium ion concentration [Ca 2+ ]i were elevated, while superoxide dismutase (SOD) and mitochondrial membrane potential (MMP) were decreased. The ratio of apoptotic and necrotic cells and intracellular lactate dehydrogenase (LDH) release were increased by Cd or BDE-47 exposure, and was aggravated by co-exposure, and was attenuated by ROS scavenger N-Acetyl- L -cysteine (NAC). NLRP3 inflammasome and pyroptosis pathway-related genes of NLRP3, adaptor molecule apoptosis-associated speck-like protein (ASC), caspase-1, interleukin-18 (IL-18) and IL-1β were elevated, while gasdermin D (GSDMD) was down-regulated, and protein levels of NLRP3, cleaved caspase-1 and cleaved GSDMD were increased, most of which were relieved by NAC. Our data demonstrate that exposure to Cd and BDE-47 induces mitochondrial dysfunction and triggers NLRP3 inflammasome and GSDMD-dependent pyroptosis leading to nephrotoxicity, and co-exposure exacerbates this effect, which could be attenuated by inhibiting ROS. This study provides a further mechanistic understanding of kidney damage, and co-exposure impact is worthy of concern and should be considered to improve the accuracy of environmental health assessment.
研究领域:
毒理学
·
环境健康
·
细胞生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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