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TLR4激动剂
DYES AND PIGMENTS · 2023 · IF 4.5

Naphthyridine-based neutral fluorescent probes for dynamic monitoring lipid droplet polarity

Meng-Nan Li,Jing-Yu Zhao,Gang Zhang,Yu-Jie Xu,Jian-Feng Ge,Ru Sun

In this paper, several novel nitrogen-containing heterocycle dyes 1a-c with large conjugated planar structures based on naphthyridine derivatives were designed and synthesized, which had excellent optical properties and biological applications. Optical test showed the maximum absorption wavelengths of 1a-c were in the range of 443–485 nm, while the maximum emission wavelengths located at 523–610 nm in difference solvents. Furthermore, they exhibited polarity related fluorescence intensity changes with high fluorescence quantum yields, even up to 88% ( 1a in THF). Moreover, the transient absorption spectra revealed the excited-state lifetime of dye 1a became shorter with the increase of solvent polarity. Density functional theory calculations are also used to help explain the effect of the polarity of solvents on their fluorescence properties. Interestingly, the dyes 1a-c were somewhat toxic to cancer cells, while had an obvious growth-promoting effect on normal cells. Additionally, 1a-c with excellent lipid droplet (LD) targeting could be used for long-term observation of targeted cellular lis) hysiological activity and further applied to dynamic monitoring of changes in LDs polarity stimulated by TLR4 activator (LPS) in living cells. Overall, the excellent optical properties and biocompatibility of 1a-c indicate that they can serve as fluorescent probes for biological applications, and the results have important implications for understanding the physiological functions of LDs, especially in terms of morphological and polar changes.

研究领域: 生物化学 · 细胞生物学 · 分子生物学
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BIOMATERIALS · 2023 · IF 14

Glucosylation endows nanoparticles with TLR4 agonist capability to trigger macrophage polarization and augment antitumor immunity

Li Liu,Shengxiang Fu,Wencheng Zhu,Zhongyuan Cai,Yingzi Cao,Yubing Huang,Li Yang,Xiaomin Fu,Rongrong Jin,Chunchao Xia,Yunjiao Zhang,Su Lui,Qiyong Gong,Bin Song,Longping Wen,James M. Anderson,Hua Ai

Carbohydrates have emerged as promising candidates for immunomodulation , however, how to present them to immune cells and achieve potent immunostimulatory efficacy remains challenging. Here, we proposed and established an effective way of designing unique glyconanoparticles that can amplify macrophage-mediated immune responses through structural mimicry and multiple stimulation. We demonstrate that surface modification with glucose can greatly augment the immunostimulatory efficacy of nanoparticles , comparing to mannose and galactose . In vitro studies show that glucosylation improved the pro-inflammatory efficacy of iron oxide nanoparticles (IONPs) by up to 300-fold, with the immunostimulatory activity of glucosylated IONPs even surpassing that of LPS under certain conditions. In vivo investigation show that glucosylated IONPs elicited increased antitumor immunity and achieved favorable therapeutic outcomes in multiple murine tumor models. Mechanistically, we proposed that glucosylation potentiated the immunostimulatory effect of IONPs by amplifying toll-like receptors 4 (TLR4) activation. Specifically, glucosylated IONPs directly interacted with the TLR4-MD2 complex, resulting in M1 macrophage polarization and enhanced antitumor immunity via activation of NF-κB, MAPK , and STAT1 signaling pathways . Our work provides a simple modification strategy to endow nanoparticles with potent TLR4 agonist effects, which may shed new light on the development of artificial immune modulators for cancer immunotherapy .

研究领域: 癌症免疫疗法 · 纳米技术 · 免疫学
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Nano Today · 2021 · IF 20.722

Boosting innate and adaptive antitumor immunity via a biocompatible and carrier-free nanovaccine engineered by the bisphosphonates-metal coordination

Mengmeng Qin,Minghui Li,Ge Song,Canyu Yang,Peiyao Wu,Wenbing Dai,Hua Zhang,Xueqing Wang,Yiguang Wang,Demin Zhou,Bing He,Qiang Zhang

Most of tumor vaccines currently focus on inducing adaptive immunity, while the antitumor potential of innate immunity is getting more attentions. In an attempt to recruit both innate and adaptive immunity, bisphosphonates (BPs) as a type of orthopaedics drugs with biosafety was applied in an antitumor vaccine here as an innate immune regulator. BPs and calcium themselves shaped the biodegradable nanocarrier via their coordination (CaBPs), which could load peptide antigens due to its hydrophilicity and be stabilized by surface lipids including a TLR4 agonist (nanovaccine). As results, the incorporation of BPs triggered the proliferation and activation of DCs and innate-like γδT cells, while the nanovaccine enhanced antigen presentation and specific lysis of tumor cells. The combination of nanovaccine and anti-PD-1 achieved a 50% total disappearance of tumor. In a prophylactic study, no any tumor occurred in nanovaccine group during a 110 day study with 3 time tumor challenges. Generally, this study validates the double antitumor immunities and provides a very promising approach for clinic application.

CAS / MDL: 121268-17-5
研究领域: 免疫学 · 肿瘤学 · 药理学 · 纳米技术
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CARBOHYDRATE POLYMERS · 2024 · IF 10.7

A glucuronogalactomannan isolated from Tetrastigma hemsleyanum Diels et Gilg: Structure and immunomodulatory activity

Zian Mao,Liu Yang,Yishan Lv,Yuchi Chen,Mingyuan Zhou,Chengnan Fang,Bingqi Zhu,Fangmei Zhou,Zhishan Ding

A novel acidic glucuronogalactomannan (STHP-5) was isolated from the aboveground part of Tetrastigma hemsleyanum Diels et Gilg with a molecular weight of 3.225 × 10 5  kDa. Analysis of chain conformation showed STHP-5 was approximately a random coil chain. STHP-5 was composed mainly of galactose, mannose, and glucuronic acid. Linkages of glycosides were measured via methylation analysis and verified by NMR. Based on the structural characterization, the repeat unit of STHP-5 was proposed. In vitro, STHP-5 induced the production of nitric oxide (NO) and secretion of IL-6, MCP-1, and TNF-α in RAW264.7 cells, indicating STHP-5 had stimulatory activity on macrophages. STHP-5 was proven to function as a TLR4 agonist by inducing the secretion of secreted embryonic alkaline phosphatase (SEAP) in HEK-Blue™-hTLR4 cells. The TLR4 activation capacity was quantitatively measured via EC50, and it showed purified polysaccharides had stronger effects (lower EC50) on activating TLR4 compared with crude polysaccharides. In conclusion, our findings suggest STHP-5 may be a novel immunomodulator.

CAS / MDL: 7789-20-0
研究领域: 药理学 · 免疫学 · 生物化学 · 分子生物学
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