Frontiers in Pharmacology
·
2025
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IF 4.8
Yu Deng,Ruobing Fu,Yaqi Shang,Mengting Hu,Xirui Xin,Yubo Hou,Weixian Yu,Xinchan Liu
Introduction: Periodontitis is a chronic inflammatory disease closely associated with mitochondrial dysfunction. Uncoupling protein 2 (UCP2), located in the inner membrane of mitochondria, reduces mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) synthesis by promoting proton leakage across the membrane. This leads to decreased energy metabolism efficiency, impairing cellular glucose uptake, and disrupting intracellular energy balance. Genipin (GP), a recognized UCP2 inhibitor, exhibits anti-inflammatory and antioxidant properties. This study aimed to investigate the specific role of GP in periodontal tissue redox signaling and the potential mechanism of UCP2 in the development of periodontitis.Methods: In this study, we constructed a model of H2O2-induced oxidative stress in human periodontal ligament cells (hPDLCs). In vivo, a rat periodontitis model was established to evaluate the effects and mechanisms of GP in alleviating oxidative damage in periodontal tissues and cells.Results: Cell experiments showed that GP effectively alleviated H2O2-induced mitochondrial dysfunction and oxidative damage in hPDLCs by inhibiting UCP2 expression and function, restoring cell viability, and reducing cell apoptosis. Additionally, GP intervention increased the expression of glucose transporter 4 (GLUT4), thereby promoting cellular glucose uptake. The results of animal experiments demonstrated that GP intervention reduced alveolar bone resorption and periodontal tissue destruction in rats with periodontitis, inhibited osteoclast differentiation, improved mitochondrial dysfunction in periodontal tissue, promoted GLUT4 expression, and reduced oxidative stress levels and cell apoptosis.Discussion: GP regulates oxidative damage in periodontal tissues by maintaining mitochondrial homeostasis, promoting glucose transporter expression, and enhancing glucose uptake, with UCP2 playing a central role.
研究领域:
口腔医学
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分子生物学
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DOI
PubMed
高影响因子
PHYTOMEDICINE
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2024
·
IF 6.7
Fukui Shen,Wen Yang,Guoqing Luan,Jiamin Peng,Zhenqiang Li,Jie Gao,Yuanyuan Hou,Gang Bai
Background Catalpol (CAT), a naturally occurring iridoid glycoside sourced from the root of Rehmannia glutinosa , affects mitochondrial metabolic functions. However, the mechanism of action of CAT against pyrexia and its plausible targets remain to be fully elucidated. Purpose This study aimed to identify the specific targets of CAT for blocking mitochondrial thermogenesis and to unveil the unique biological mechanism of action of the orthogonal binding mode between the hemiacetal group and lysine residue on the target protein in vivo . Methods Lipopolysaccharide (LPS)/ carbonyl cyanide 3-chlorophenylhydrazone (CCCP)-induced fever models were established to evaluate the potential antipyretic effects of CAT. An alkenyl-modified CAT probe was designed to identify and capture potential targets. Binding capacity was tested using in-gel imaging and a cellular thermal shift assay. The underlying antipyretic mechanisms were explored using biochemical and molecular biological methods. Catalpolaglycone (CA) was coupled with protein profile identification and molecular docking analysis to evaluate and identify its binding mode to UCP2. Results After deglycation of CAT in vivo , the hemiacetal group in CA covalently binds to Lys239 of UCP2 in the mitochondria of the liver via an ɛ-amine nucleophilic addition. This irreversible binding affects proton leakage and improves mitochondrial membrane potential and ADP/ATP transformation efficiency, leading to an antipyretic effect. Conclusion Our findings highlight the potential role of CA in modulating UCP2 activity or function within the mitochondria and open new avenues for investigating the therapeutic effects of CA on mitochondrial homeostasis.
研究领域:
药理学
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分子生物学
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生物化学
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PubMed
高影响因子
JOURNAL OF INTERFERON AND CYTOKINE RESEARCH
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2022
·Vol. 42
·期 6
·267-278
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IF 3.657
Jing Hu,Yan Cheng,Ping Chen,Zhaoqi Huang,Liqi Yang
Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction without overt central nervous system infection. Caffeine citrate has therapeutic effect on different brain diseases, while its role in SAE remains unclear. The expression levels of interleukin (IL)-18 and IL-1β were upregulated in the cerebrospinal fluid of the subjects. In this study, a rat model of SAE was established by cecal ligation and puncture. Caffeine citrate inhibited SAE-induced neuronal apoptosis and astrocytic activation, decreased reactive oxygen species (ROS) generation, and elevated mitochondrial membrane potential (MMP) level in the cerebral cortex. In vitro, primary astrocytes were isolated from rat cerebral cortex and incubated with lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Caffeine citrate reduced ROS and MMP levels and mitochondrial complex enzyme activities in LPS plus IFN-γ-induced astrocytes. Moreover, caffeine citrate inhibited the activation of nucleotide-binding and oligomerization domain (NOD)-like receptor (NLRP3) inflammasome and decreased the production of IL-1β and IL-18 in vivo and in vitro. Notably, caffeine citrate promoted UCP2 expression in astrocytes. The neuroprotective role of UCP2 has been reported in several experimental brain diseases. These results suggest that caffeine citrate inhibits neuronal apoptosis, astrocytic activation, mitochondrial dysfunction in rat cerebral cortex, thereby alleviating SAE. The protection of caffeine citrate against SAE may be achieved by the UCP2-mediated NLRP3 pathway inhibition in astrocytes.
研究领域:
神经科学
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免疫学
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药理学
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细胞生物学
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DOI
PubMed
高影响因子
ANTIOXIDANTS & REDOX SIGNALING
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2024
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IF 5.9
Yecheng Wang,Caiyun Huang,Xiaoying Wang,Rong Cheng,Xue Li,Jiahao Wang,Lu Zhang,Fuhao Li,Hao Wang,Xinyu Li,Yi Li,Yiqing Xia,Jian Cheng,Xiaofan Pan,Jia Jia,Guo-dong Xiao
Aims: Succinate, a metabolite in the tricarboxylic acid cycle, is increasingly recognized to play essential roles in inflammation by functioning either as an intracellular or extracellular signaling molecule. However, the role and mechanisms of succinate in inflammation remain elusive. Here, we investigated the mechanism underlying the effects of succinate on neuroinflammation in intracerebral hemorrhage (ICH) models. Results: We unexpectedly found that succinate robustly inhibited neuroinflammation and conferred protection following ICH. Mechanistically, oxidation of succinate by succinate dehydrogenase (SDH) drove reverse electron transport (RET) at mitochondrial complex I, leading to mitochondrial superoxide production in microglia. Complex I-derived superoxide, in turn, activated uncoupling protein 2 (UCP2). By using mice with specific deletion of UCP2 in microglia/macrophage, we showed that UCP2 was needed for succinate to inhibit neuroinflammation, confer protection, and activate downstream AMP-activated protein kinase (AMPK) following ICH. Moreover, knockdown of SDH, complex I or AMPK abolished the therapeutic effects of succinate following ICH. Innovation and Conclusion: We provide evidence that driving complex I RET to activate UCP2 is a novel mechanism of succinate intracellular signaling and a mechanism underlying the inhibition of neuroinflammation by succinate. Key words: succinate; uncoupling protein 2; microglia; neuroinflammation; intracerebral hemorrhage
研究领域:
神经科学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
MOLECULAR NEUROBIOLOGY
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2026
·Vol. 63
·期 1
·650
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IF 5.5
Guo Yaoxue,Wang Xueyan,Zhang Lixiang,Liu Xing,Lu Pu,Liang Furu,Wu Jing,Zhao Junli,Hai Yan
Alzheimer’s disease (AD) is associated with mitochondrial dysfunction and impaired energy metabolism in astrocytes. Although ghrelin is known to exert neuroprotective effects, the mechanisms through which it modulates astrocyte bioenergetics under AD-like conditions remain incompletely defined. In primary astrocytes treated with Aβ 25-35 oligomers, ghrelin attenuated mitochondrial damage, reducing ROS and enhancing mitochondrial membrane potential (ΔΨm) and respiratory complex activities. Glycolytic function was partially restored, as evidenced by upregulation of key enzymes, increased glucose uptake, lactate release, and NAD + /NADH ratio. Ghrelin inhibited autophagosome formation while enhancing mitophagy (increased LC3II/I and Parkin) and suppressed inflammation. In co-culture models, these metabolic improvements enhanced astrocytic support for neurons, reducing apoptosis and promoting neurite growth, an effect abolished by the glycolytic inhibitor 2-DG. Mechanistically, ghrelin upregulated uncoupling protein 2 (UCP2), which inhibited forkhead box protein O1 (FOXO1) nuclear translocation. In Aβ 25-35 -injected mice with UCP2 or FOXO1 modulation, ghrelin improved cognitive performance and reduced pathology, effects that were negated by UCP2 knockdown and partially rescued by FOXO1 knockdown. In conclusion, ghrelin ameliorates Aβ-induced astrocyte dysfunction involving the UCP2-FOXO1 pathway, partially restoring mitochondrial integrity, glycolytic metabolism, and neurotrophic support, suggesting its therapeutic potential.
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DOI
PubMed
高影响因子
JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY
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2026
·Vol. 40
·期 4
·e70808
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IF 3.6
Hailong Du,Xiaoliang Wang,Jianping Sun,Xiaosong Liu,Lei Zhao,Haoming Guo,Jianliang Wu,Jiankai Yang
This paper sought to determine whether uncoupling protein 2 (UCP2) regulates the immune phenotype of TAMs by modulating its own mitochondrial metabolic homeostasis in glioblastoma (GBM) cells, thereby influencing anti-tumor treatment response. This study evaluated UCP2 levels in clinical GBM samples and cell lines based on public databases, immunohistochemistry, RT-qPCR, and Western blot. A cell model with specific knockdown of UCP2 was constructed, and cell proliferation, migration and invasion, and apoptosis were detected. ATP measurement, Seahorse analysis, JC-1 staining, H2DCFDA, and MitoSOX staining were employed to assess mitochondrial metabolic function and ROS levels in GBM cells. A GBM-THP-1 co-culture system was established to evaluate the impact of UCP2 knockdown in GBM cells on macrophage polarization. A subcutaneous tumor model was established to evaluate the synergistic effect of UCP2 silencing + anti-PD-L1 therapy. UCP2 was upregulated in GBM tissues and accompanied by increased infiltration of M2-type TAMs. Specific knockdown of UCP2 in GBM cells inhibited cell proliferation and invasion, promoted apoptosis, and induced metabolic reprogramming by inhibiting mitochondrial energy metabolism, reducing mitochondrial membrane potential, and ROS accumulation. Co-culture with GBM cells with UCP2 knockdown promoted macrophage polarization toward the M1 type. UCP2 knockdown + anti-PD-L1 antibody inhibited GBM growth and increased the infiltration of M1-type TAMs. Knockdown of UCP2 in GBM cells reshapes the tumor microenvironment by regulating the tumor cell mitochondrial metabolism, thereby influencing their interaction with TAMs. This promotes M1-type repolarization and enhances the efficacy of anti-tumor treatment, making it a potential therapeutic target.
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高影响因子
Neuroscience Bulletin
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2022
·Vol. 38
·期 11
·1347-1364
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IF 5.271
Yu Jie,Cheng Yao,Cui Yaru,Zhai Yujie,Zhang Wenshen,Zhang Mengdi,Xin Wenyu,Liang Jia,Pan Xiaohong,Wang Qiaoyun,Sun Hongliu
An increased level of reactive oxygen species is a key factor in neuronal apoptosis and epileptic seizures. Irisin reportedly attenuates the apoptosis and injury induced by oxidative stress. Therefore, we evaluated the effects of exogenous irisin in a kainic acid (KA)-induced chronic spontaneous epilepsy rat model. The results indicated that exogenous irisin significantly attenuated the KA-induced neuronal injury, learning and memory defects, and seizures. Irisin treatment also increased the levels of brain-derived neurotrophic factor (BDNF) and uncoupling protein 2 (UCP2), which were initially reduced following KA administration. Furthermore, the specific inhibitor of UCP2 (genipin) was administered to evaluate the possible protective mechanism of irisin. The reduced apoptosis, neurodegeneration, and spontaneous seizures in rats treated with irisin were significantly reversed by genipin administration. Our findings indicated that neuronal injury in KA-induced chronic epilepsy might be related to reduced levels of BDNF and UCP2. Moreover, our results confirmed the inhibition of neuronal injury and epileptic seizures by exogenous irisin. The protective effects of irisin may be mediated through the BDNF-mediated UCP2 level. Our results thus highlight irisin as a valuable therapeutic strategy against neuronal injury and epileptic seizures.
研究领域:
神经科学
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药理学
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分子生物学
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癫痫研究
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PubMed
高影响因子
ACS Nano
·
2023
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IF 17.1
Wenshuai Hao,Ruitao Cha,Mingzheng Wang,Juanjuan Li,Hongbo Guo,Ran Du,Fengshan Zhou,Xingyu Jiang
Intestinal metabolism-related diseases, such as constipation, inflammatory bowel disease, irritable bowel syndrome, and colorectal cancer, could be associated with the dysfunction of intestinal mitochondria. The mitochondria of intestinal epithelial cells are of great significance for promoting intestinal motility and maintaining intestinal metabolism. It is necessary for the prophylaxis and therapy of intestinal metabolism-related diseases to improve mitochondrial function. We investigated the effect of 4,6-diamino-2-pyrimidinethiol-modified gold nanoparticles (D-Au NPs) on intestinal mitochondria and studied the regulatory role of D-Au NPs on mitochondria metabolism-related disease. D-Au NPs improved the antioxidation capability of mitochondria, regulated the mitochondrial metabolism, and maintained intestinal cellular homeostasis via the activation of AMPK and regulation of PGC-1α with its downstream signaling (UCP2 and DRP1), enhancing the intestinal mechanical barrier. D-Au NPs improved the intestinal mitochondrial function to intervene in the emergence of constipation, which could help develop drugs to treat and prevent mitochondrial metabolism-related diseases. Our findings provided an in-depth understanding of the mitochondrial effects of Au NPs for improving human intestinal barriers.
研究领域:
纳米技术
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药理学
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胃肠病学
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分子生物学
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治疗学
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PubMed
高影响因子
BIOMATERIALS
·
2024
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IF 12.8
Yuhuan Li,Jiayin Lv,Shuchen Liu,Zhuoran Wang,Yu Gao,Zheyuan Fan,Lei Huang,Jing Cui,Boya Zhang,Xinchen Liu,Zhuo Zhang,Te Liu,Daowei Li,Modi Yang
The role of pro-inflammatory macrophages (M1) in rheumatoid arthritis (RA) is significant, as they produce excessive cytokines. Targeting efferocytosis is a potential manner to repolarize M1 macrophages into pro-resolving M2 phenotype, which restores immune homeostasis by releasing anti-inflammatory mediators. In this study, liquid nitrogen-treated dead macrophages (DM) are employed to act as a dead cell-derived active targeted drug carrier for shikonin (SHK) and induce efferocytosis in M1 macrophages with the enhancement of SHK as an AMP-activated protein kinase (AMPK)-activator. The synergistic activation of AMPK leads to uncoupled protein 2 (UCP2) upregulation and reprograms M1 macrophages into M2 phenotypes by promoting oxidative phosphorylation. In the mouse model of collagen-induced arthritis, the intravenous administration of DM/SHK leads to a consistent transformation of M1 macrophages into the M2 phenotype within the infiltrative synovium. This transformation of macrophages results in the restoration of immune homeostasis in the synovium through an increase in the production of pro-resolving mediators. Additionally, it inhibits synovial proliferation and infiltration and provides protection against erosion of cartilage and bone. In summary, LNT-based DM serves as an active targeting drug carrier to M1 macrophages and also acts synergistically with SHK to target immunometabolism.
研究领域:
免疫学
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药理学
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风湿病学
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炎症
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药物递送系统
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DOI
PubMed
高影响因子
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