International Journal of Biological Sciences
·
2025
·Vol. 21
·期 11
·4872-4894
·
IF 10
Chen Yuxing,Tao Yong,Huang Qiu,Xu Jingtao,Wang Zhenxin,Zhang Ye,Fu Guangxu,Tan Fuqiang,Feng Keyi,Ou Yunsheng
Osteosarcoma remains a challenging malignancy with poor prognosis, particularly in metastatic cases. This study investigates the therapeutic potential and molecular mechanisms of the Hinokitiol-iron complex (Fe(hino)3) against osteosarcoma. Fe(hino)3 induced dose-dependent cell death in osteosarcoma cell lines (HOS, 143b, and K7M2) through multiple pathways. At moderate doses, Fe(hino)3 triggered ferroptosis by disrupting mitochondrial function, enhancing ROS generation and lipid peroxidation, downregulating GSS and GPX4, and upregulating HO1 and Ferritin expression. At higher doses, Fe(hino)3 activated the NLRC4/Caspase-1/GSDMD pathway, leading to pyroptosis and the release of inflammatory factors. Mechanistically, Fe(hino)3 acted as a dual-mode cell death inducer through iron overload-mediated ferroptosis and NLRC4-dependent pyroptosis while modifying the immunosuppressive tumor microenvironment. In actual clinical application, Fe(hino)3 might be used as an alternative to chemotherapy or other targeted therapies for advanced osteosarcoma at a relatively low dose to improve biosafety and reduce side effects. However, when considering it in combination with immunotherapy for advanced osteosarcoma, a relatively safe high dose is more appropriate due to the pyroptosis-mediated inflammatory response but it still needs to consider the biosafety of combination therapy. These findings provide new insights into the development of Fe(hino)3 dose-dependent therapeutic strategies for advanced osteosarcoma treatment.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
免疫学
·
生物化学
·
分子生物学
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
eNeuro
·
2024
·
IF 2.7
Yonghong Tan,Qiong Wang,Yubing Guo,Na Zhang,Yingyi Xu,Xue Bai,Jianhua Liu,Xiaobao Bi
Pyroptosis, an inflammatory Programmed cell death, has recently been found to play an important role in spinal cord injury (SCI). C-type lectin domain family 5 member A (CLEC5A), triggering receptor expressed on myeloid cells 1 (TREM1), and NLR-family CARD-containing protein 4 (NLRC4) have been reported to be associated with neuronal pyroptosis, but few studies have clarified their functions and regulatory mechanisms in SCI. In this study, CLEC5A, TREM1, and NLRC4 were highly expressed in lidocaine-induced SCI rat models, and their knockdown alleviated lidocaine-induced SCI. The elevation of proptosis related indicators LDH, ASC, GSDMD-N, IL-18, caspase-1, and IL-1β levels in SCI rats was attenuated after silencing of CLEC5A, TREM1, or NLRC4. Lidocaine-induced the decrease in cell viability and the elevation in cell death were partly reversed after CLEC5A, TREM1, or NLRC4 silencing. Lidocaine-mediated effects on the levels of LDH, ASC, GSDMD-N, IL-18, caspase-1, and IL-1β in lidocaine-induced PC-12 cells were weakened by downregulating CLEC5A, TREM1, or NLRC4. CLEC5A could interact with TREM1 to mediate NLRC4 expression, thus accelerating neuronal pyroptosis, ultimately leading to SCI exacerbation. In conclusions, CLEC5A interacted with TREM1 to increase NLRC4 expression, thus promoting neuronal pyroptosis in rat SCI models, providing new insights into the role of neuronal pyroptosis in SCI.Significance statement Pyroptosis has been reported to be involved in SCI. Higher levels of CLEC5A, TREM1, and NLRC4 associated with neuronal pyroptosis. However, the role and regulatory mechanism of CLEC5A, TREM1, and NLRC4 in SCI were not clear. Here, high expression of CLEC5A, TREM1, and NLRC4 was observed in lidocaine-induced SCI rat models. CLEC5A could interact with TREM1 to enhance the expression of NLRC4, thus accelerating neuronal pyroptosis in rat SCI models. These findings identify CLEC5A, TREM1, and NLRC4 as potential therapeutic targets for SCI.
研究领域:
神经科学
·
细胞生物学
·
炎症
·
脊髓损伤
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PLoS Pathogens
·
2021
·Vol. 17
·期 12
·e1010145
·
IF 6.823
Kaiyu Chen,Siyuan Zhang,Yina Shao,Ming Guo,Weiwei Zhang,Chenghua Li
Many members of the nucleotide-binding and oligomerization domain (NACHT)- and leucine-rich-repeat-containing protein (NLR) family play crucial roles in pathogen recognition and innate immune response regulation. In our previous work, a unique and Vibrio splendidus -inducible NLRC4 receptor comprising Ig and NACHT domains was identified from the sea cucumber Apostichopus japonicus , and this receptor lacked the CARD and LRR domains that are typical of common cytoplasmic NLRs. To better understand the functional role of AjNLRC4, we confirmed that AjNLRC4 was a bona fide membrane PRR with two transmembrane structures. AjNLRC4 was able to directly bind microbes and polysaccharides via its extracellular Ig domain and agglutinate a variety of microbes in a Ca 2+ -dependent manner. Knockdown of AjNLRC4 by RNA interference and blockade of AjNLRC4 by antibodies in coelomocytes both could significantly inhibit the phagocytic activity and elimination of V . splendidus . Conversely, overexpression of AjNLRC4 enhanced the phagocytic activity of V . splendidus , and this effect could be specifically blocked by treatment with the actin-mediated endocytosis inhibitor cytochalasin D but not other endocytosis inhibitors. Moreover, AjNLRC4-mediated phagocytic activity was dependent on the interaction between the intracellular domain of AjNLRC4 and the β-actin protein and further regulated the Arp2/3 complex to mediate the rearrangement of the cytoskeleton and the polymerization of F-actin. V . splendidus was found to be colocalized with lysosomes in coelomocytes, and the bacterial quantities were increased after injection of chloroquine, a lysosome inhibitor. Collectively, these results suggested that AjNLRC4 served as a novel membrane PRR in mediating coelomocyte phagocytosis and further clearing intracellular Vibrio through the AjNLRC4-β-actin-Arp2/3 complex-lysosome pathway.
Vibrio splendidus is ubiquitously present in marine environments and in or on many aquaculture species and is considered to be an important opportunistic pathogen that has caused serious economic losses to the aquaculture industry worldwide. Phagocytosis is the first step of pathogen clearance and is triggered by specific interactions between host pattern recognition receptors (PRRs) and pathogen-associated molecular patterns (PAMPs) from invasive bacteria. However, the mechanism that underlies receptor-mediated V . splendidus phagocytosis is poorly understood. In this study, an atypical AjNLRC4 receptor without LRR and CARD domains was found to serve as the membrane receptor for V . splendidus , not the common cytoplasmic NLRs. The Ig domain of AjNLRC4 is replaced with a conventional LRR domain to bind V . splendidus , and the intracellular domain of AjNLRC4 specifically interacts with β-actin to mediate V . splendidus endocytosis in an actin-dependent manner. Endocytic V . splendidus is ultimately degraded in phagolysosomes. Our findings will contribute to the development of novel strategies for treating V . splendidus infection by modulating the actin-dependent endocytosis pathway.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMOSPHERE
·
2023
·
IF 8.8
Zhen-Ning Zhang,Dan-Lei Yang,Hai Liu,Jue Bi,Ya-Bo Bao,Jiao-Yang Ma,Qin-Xiang Zheng,Dao-Lei Cui,Wei Chen,Ping Xiang
Tris(2-chloroisopropyl) phosphate (TCPP) and Tris(2-chloroethyl) phosphate (TCEP) are the widely used organophosphorus flame retardants indoors and easily accessible to the eyes as the common adhesive components of dust and particle matter, however, hardly any evidence has demonstrated their corneal toxicity. In this study, the adverse effects of TCPP, TCEP, and TCPP + TCEP exposure on human corneal epithelial cells (HCECs) were investigated. The cell viability and morphology, intracellular reactive oxygen species (ROS), cell cycle, and the expressions of cell cycle and pyroptosis-related genes were assessed to explain the underlying mechanisms. Compared to individual exposure, co-exposure to TCPP 20 +TCEP 20 showed higher cytotoxicity with a sharp decrease of >30% in viability and more serious oxidative damage by increasing ROS production to 110.92% compared to the control group. Furthermore, the cell cycle arrested at the S phase (36.20%) was observed after combined treatment, evidenced by the upregulation of cyclin D1 , CDK2 , CDK4 , CDK6 , p21, and p27 . Interestingly, pyroptosis-related genes GSDMD , Caspase-1 , NLRP3 , IL-1β , IL-18 , NLRP1, and NLRC4 expressions were promoted with cell swelling and glowing morphology. Oxidative stress and cell cycle arrest probably acted as a key role in TCPP 20 +TCEP 20 -induced cytotoxicity and pyroptosis in HCECs. Our results suggested that TCPP 20 +TCEP 20 co-exposure induced severer corneal damage, further illustrating its significance in estimating indoor health hazards to humans.
研究领域:
毒理学
·
细胞生物学
·
眼科学
·
环境健康
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）