Molecular Medicine Reports
·
2019
·Vol. 20
·期 3
·2135-2142
·
IF 1.851
Ming Yu,Demei Zang,Yuhao Xu,Jie Meng,Shengnan Qian
Advanced glycation end products (AGEs) are important pathogenic substances involved in diabetes mellitus (DM) and its complications. AGEs also serve important roles in promoting the development of Alzheimer's disease (AD). Macrophage migration inhibitory factor (MIF), an inflammatory stimulant and a pathogenic factor involved in DM, was previously reported to be present at increased levels in the cerebrospinal fluid of patients with AD and mild cognitive impairment compared with age‑matched healthy controls. By investigating the association between AGEs and MIF, and the effects of neuroinflammation on AD, the present study aimed to increase understanding of the specific molecular mechanisms involved in the pathogenesis of DM and AD, and the connection between these diseases. PC12 cells were cultured in vitro; the levels of MIF mRNA and protein were determined using reverse transcription‑quantitative (RT‑q)PCR and western blot analyses. The optimal concentrations of AGEs and amyloid β 1‑40 (Aβ1‑40) were also determined in the cell model of AD using Cell Counting Kit‑8 and MTT assays. Cell numbers and morphological changes were observed following the treatment of Aβ1‑40‑stimulated PC12 cells with AGEs and the MIF inhibitor (S,R)‑3‑(4‑hydroxyphenyl)‑4,5‑dihydro‑5‑isoxazole acetic acid methyl ester (ISO‑1). The mRNA expression levels of interleukin (IL)‑1β, IL‑6, tumor necrosis factor‑α (TNF‑α) and MIF were determined via RT‑qPCR analysis. The results showed that the levels of MIF mRNA and protein were significantly increased in cells treated with AGEs compared with the control group. In the AD model group, the inhibition of PC12 cell growth was significantly increased, and the mRNA expression levels of IL‑1β, IL‑6, TNF‑α and MIF were also increased. Compared with treatment with AGEs alone, the combination of AGEs treatment with ISO‑1 significantly improved the survival rate and resulted in the reduced expression of inflammatory mediators in the AD cell model. Thus, ISO‑1 reduced AGEs‑mediated damage in the AD cell model. This may be a consequence of AGEs‑mediated MIF expression promoting neuritis in the AD cell model, whereas ISO‑1 decreased the expression of neuroinflammatory mediators.
研究领域:
医学
·
神经科学
·
分子生物学
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DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2025
·
IF 14.6
Wen Guo,Cheng Hu,Yue Wang,Wen Zhang,Shaomin Zhang,Jin Peng,Yunbing Wang,Jinhui Wu
Stroke is a global disease that seriously threatens human life. The pathological mechanisms of ischemic stroke include neuroinflammation, oxidative stress, and the destruction of blood vessels at the lesion site. Here, a biocompatible in situ hydrogel platform was designed to target multiple pathogenic mechanisms post-stroke, including anti-inflammation, anti-oxidant, and promotion of angiogenesis. Double-crosslinked responsive multifunctional hydrogels could quickly respond to the pathological microenvironment of the ischemic damage site and mediate the delivery of nitric oxide (NO) and ISO-1 (inhibitor of macrophage migration inhibitory factor, MIF). The hydrogel demonstrated good biocompatibility and could scavenge reactive oxygen species (ROS) and inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-10 (IL-10), and MIF. In a mouse stroke model, hydrogels, when situated within the microenvironment of cerebral infarction characterized by weak acidity and elevated ROS release, would release anti-inflammatory nanoparticles rapidly that exert an anti-inflammatory effect. Concurrently, NO was sustained release to facilitate angiogenesis and provide neuroprotective effects. Neurological function was significantly improved in treated mice as assessed by the modified neurological severity score, rotarod test, and open field test. These findings indicate that the designed hydrogel held promise for sustained delivery of NO and ISO-1 to alleviate cerebral ischemic injury by responding to the brain’s pathological microenvironment.
研究领域:
神经科学
·
生物医学工程
·
药理学
·
材料科学
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2026
·
IF 10.4
Chen Chuan-jun,Guo Ding-wen,Yuan Qing-yun,Zhuo You-qiong,Yang Shi-fen,Xu Hao-min,Wang You-rong,Guan Xiao-hui,Deng Ke-yu,Xin Hong-bo
Macrophage migration inhibitory factor (MIF) is a cytokine that possesses multiple enzymatic activities, such as keto-enol tautomerase and thiol-oxidoreductase. We previously found that lack of MIF tautomerase activity significantly alleviated high fat diet (HFD)-induced obesity in mice. In this study, we investigated the regulatory mechanisms of MIF tautomerase in obesity. HFD-induced obese mouse model was established. Adipogenic differentiation was induced in mouse preadipocyte cell line 3T3-L1 and mouse adipose-derived mesenchymal stem cells (ADSCs) in vitro. We showed that MIF tautomerase inhibitors ISO-1 or 4-IPP dose-dependently promoted lipid degradation and mitochondrial thermogenesis by enhancing basal oxygen consumption rate and proton leak, accompanied by increased expression of browning markers (UCP1, PGC-1α, DIO2, CD137) in 3T3-L1 cells under adipogenic induction conditions. In HFD-induced obese mice, administration of 4-IPP (5, 10 mg/kg, i.p.) every 2 days for 12 weeks significantly ameliorated HFD-induced obesity, improved insulin sensitivity, and enhanced energy expenditure. In white adipocytes, 4-IPP (1, 5, 10 μM) dose-dependently promoted CD137 expression, and restored CD137-mediated activation of the PI3K/AKT signaling to improve lipid metabolism. CD137 deficiency abrogated the browning effect of 4-IPP in white adipocytes in vitro. CD137 −/− mice exhibited increased susceptibility to HFD-induced obesity and almost abolished the anti-obesity effects of 4-IPP. Simulation of the protein interaction revealed a direct interaction between MIF and CD137: MIF competitively bound to CD137 on white adipocytes with the endogenous ligand of CD137, which was further confirmed by co-immunoprecipitation. Furthermore, 4-IPP and recombinant CD137 protein inhibited the tautomerase activity of MIF in vitro. In conclusion, MIF promotes obesity by binding CD137 through its tautomerase domain, suppressing CD137-mediated the activation of the PI3K/AKT signaling. MIF tautomerase inhibitors disrupt this interaction, restore CD137 function, and enhance adipocyte browning, offering a promising therapeutic strategy for obesity management.
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PubMed
高影响因子
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