TOXICOLOGY AND APPLIED PHARMACOLOGY
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2023
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IF 3.8
Jiaxi Chen,Mengyue Pan,Jingjie Wang,Mengling Zhang,Mingmei Feng,Xiaoming Chai,Qi Zhang,Yang Sun
Hydroxysafflor yellow A (HSYA), a chalcone glycoside, is a component of Carthamus tinctorius L. and exerts anti-inflammatory and antioxidative effects. However, the therapeutic effect and the underlying mechanism of HSYA on ulcerative colitis is unclear. This study aimed to investigate the unexplored protective effects and underlying mechanisms of HSYA on UC. In vitro analyses showed that HSYA reduced the secretion of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-6 and inhibited nucleotide-binding and oligomerization domain-like receptor protein 3 (NLRP3)/gasdermin D (GSDMD)-mediated pyroptosis in lipopolysaccharide/ adenosine-5′-triphosphate (LPS/ATP)-stimulated macrophages. Gas chromatography–mass spectrometry (GC–MS) profiling of intracellular metabolites showed that HSYA reduced the increased levels of glucose, glucose 6-phosphate, and lactic acid, and inhibited the increased hexokinase 1 (HK1) expression caused by LPS/ATP stimulation. HK1 shRNA transfection further confirmed that HSYA inhibited the NLRP3/GSDMD-mediated pyroptosis via HK1 downregulation. In vivo analyses showed that HSYA drastically attenuated UC symptoms by relieving body weight loss, a decline in colon length, and inflammatory infiltration in colonic tissues induced by dextran sulfate sodium (DSS). HSYA also reduced the secretion of pro-inflammatory cytokines including IL-1β, IL-6, TNF-α, and IL-18. Moreover, HSYA inhibited HK1/NLRP3/GSDMD-mediated pyroptosis in DSS-induced colitis mice. Finally, 16S rRNA sequencing analyses of gut microbiota revealed that HSYA reversed gut microbiota dysbiosis by reducing the abundance of Proteobacteria and increasing that of Bacteroidetes. This study demonstrated that HSYA not only exerted anti-inflammatory effects by inhibiting HK1/NLRP3/GSDMD and suppressing pyroptosis but also regulated gut microbiota in mice with DSS-induced colitis. Our findings provide new experimental evidence that HSYA might be a potential candidate for treating inflammatory bowel diseases.
研究领域:
药理学
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免疫学
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微生物学
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胃肠病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2023
·
IF 19
Fan Zhao,Liying Liang,Heng Wang,Chen Wang,Dan Su,Yao Ying,Wangchang Li,Juan Li,Jingwu Zheng,Liang Qiao,Xiaozhou Mou,Shenglei Che,Jing Yu
Copper overload is a novel way to achieve copper-ion-interference therapy by disrupting copper homeostasis and treating diseases through multiple cell death pathways. However, it is difficult to reach copper overload since excess intracellular copper ions will be pumped out. Herein, copper overload is achieved by both raising cellular uptake and reducing the efflux of copper ions using hydrogen sulfide (H 2 S)-responsive copper hydroxyphosphate nanoparticles (Cu 2 (PO 4 )(OH) NPs). After immersion in an H 2 S-enriched colon cancer microenvironment, Cu 2 (PO 4 )(OH) NPs can transform into copper sulfide NPs with reduced size for higher cell entering, resulting in improved Fenton activity as well as copper ion dissociation. Reactive oxygen species generated by the Fenton reaction not only activate inflammasomes and Caspase-1 proteins, cause the cleavage of gasdermin D to induce pyroptosis, but also affect mitochondrial function and down-regulate copper exporter ATP7A to further reduce the copper excretion. The combination of higher endocytosis and lower exportation leads to maximized copper overload. Together with the efficient copper ions release, mitochondrial tricarboxylic acid cycle can be disrupted and iron-sulfur cluster proteins are downregulated, ultimately triggering cuproptosis. As both pyroptosis and cuproptosis are efficient ways to induce cell death, this study provides a novel way to realize effective tumor-targeted therapy based on H 2 S-activated copper overload with simple Cu 2 (PO 4 )(OH) NPs.
研究领域:
肿瘤学
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纳米技术
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细胞生物学
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治疗学
✓ 已验证
产品关联
DOI
高影响因子
Nature Communications
·
2024
·Vol. 15
·期 1
·1-20
·
IF 14.7
Guo Yichen,Li Yongjuan,Zhang Mengzhe,Ma Rong,Wang Yayun,Weng Xiao,Zhang Jinjie,Zhang Zhenzhong,Chen Xiaoyuan,Yang Weijing
The limited efficacy of cancer immunotherapy occurs due to the lack of spatiotemporal orchestration of adaptive immune response stimulation and immunosuppressive tumor microenvironment modulation. Herein, we report a nanoplatform fabricated using a pH-sensitive triblock copolymer synthesized by reversible addition-fragmentation chain transfer polymerization enabling in situ tumor vaccination and tumor-associated macrophages (TAMs) polarization. The nanocarrier itself can induce melanoma immunogenic cell death (ICD) via tertiary amines and thioethers concentrating on mitochondria to regulate metabolism in triggering endoplasmic reticulum stress and upregulating gasdermin D for pyroptosis as well as some features of ferroptosis and apoptosis. After the addition of ligand cyclic arginine-glycine-aspartic acid (cRGD) and mannose, the mixed nanocarrier with immune adjuvant resiquimod encapsulation can target B16F10 cells for in situ tumor vaccination and TAMs for M1 phenotype polarization. In vivo studies indicate that the mixed targeting nanoplatform elicits tumor ICD, dendritic cell maturation, TAM polarization, and cytotoxic T lymphocyte infiltration and inhibits melanoma volume growth. In combination with immune checkpoint blockade, the survival time of mice is markedly prolonged. This study provides a strategy for utilizing immunoactive materials in the innate and adaptive immune responses to augment cancer therapy.
研究领域:
癌症研究
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纳米技术
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免疫学
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药学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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