PHARMACOLOGICAL RESEARCH
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2026
·
IF 12.2
Shixian Pi,Wanling Liu,Junyong Zhao,Hui Chen,Xianbin Luo,Shaofa Wu,Jiarou Song,Xun Chen,Xue Li,Wenjian Luo,Yirui Wang,Chuan Liu,Jun Ren,Tian Li,He Liu,Xiaoyong Tong,Zhexue Qin
Vascular calcification arises from osteogenic transdifferentiation of vascular smooth muscle cells (VSMC) driven by disordered calcium signaling. Sarcoplasmic/ER calcium ATPase 2 (SERCA2) maintains intracellular calcium homeostasis. Irreversible oxidation of SERCA2 Cys 674 (C674) indicates SERCA2 dysfunction. The impact of SERCA2 dysfunction on vascular calcification remains poorly understood. Here, we demonstrate that oxidized SERCA2 C674, a SERCA2 dysfunction marker, was elevated in the calcified arteries of mice and chronic kidney disease (CKD) patients. Heterozygous SERCA2 Cys674Ser knock-in (SKI) mice, a SERCA2 dysfunction model, exhibited aggravated aortic calcification in cholecalciferol (VitD3)-overloaded and 5/6 nephrectomy-induced CKD mice. SERCA2 dysfunction exacerbates calcification, mitochondrial impairment and calcium overload in cultured VSMC. Mechanistically, SERCA2 dysfunction increased mitochondria-associated endoplasmic reticulum membrane (MAM) formation. Furthermore, outer-mitochondrial translocator protein (TSPO) was identified to facilitate SERCA2 coupling to the IP3R1-Grp75-VDAC1-MCU complex at MAM. TSPO knockdown alleviated SERCA2 dysfunction-induced MAM formation and vascular calcification in SKI mice and cultured SKI VSMC, while TSPO overexpression aggravated these effects. Inhibition of the downstream mitochondrial calcium uniporter (MCU) reduced mitochondrial calcium overload and thus alleviated the pro-calcific effects of TSPO in SKI VSMC. In conclusion, SERCA2 dysfunction promotes TSPO-dependent MAM formation, which couples SERCA2 to the IP3R1-Grp75-VDAC1-MCU complex, causing mitochondrial impairment and calcium overload. This study uncovers the pivotal role of SERCA2 during vascular calcification, delineates the novel components of the MAM complex, and highlights potential therapeutic targets of vascular calcification.
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PubMed
高影响因子
Journal of Neuroinflammation
·
2026
·Vol. 23
·期 1
·212
·
IF 11.5
Song Huanhuan,Zhu Zhibao,Xiao Limei,Zhao Qiuping,Li Chun,Lv Aowei,Yu Xintong,Gao Zhuyu,Lin Jie,Wang Youliang,Zhang Yuanyuan,Zhang Lijie,Li Runyun,Yao Shaobo,Cui Mengchao,Lin Yi,Fu Ying,Yong V. Wee,Li Rui
Neuroinflammation is a core pathological process in multiple central nervous system diseases. Although positron emission tomography (PET) targeting the translocator protein (TSPO) (e.g., ¹⁸F-DPA-714) is widely used for in vivo inflammatory imaging, the cellular heterogeneity and functional states underlying its imaging signals remain unclear, severely limiting its mechanistic research and clinical translational value. This study used the multifunctional fluorescent TSPO probe (Cy5-PEG3-DPA714) to establish a multidimensional decoding framework that enables systematic analysis of the TSPO signal in neuroinflammation across in vivo, tissue, and single-cell levels. Multiple animal models demonstrated the probe’s ability to dynamically monitor acute and chronic neuroinflammation noninvasively in vivo. Histopathology confirmed that the TSPO signal mainly comes from activated Iba1 + microglia. Using the probe’s fluorescence properties, we effectively isolated specific microglial subpopulations with distinct TSPO signaling profiles via flow cytometry. Single-cell analysis revealed that the TSPO signal is specifically enriched in a microglia subpopulation with TSPO probe high . Importantly, this subpopulation shares features with disease-associated microglia (DAM), exhibiting a robust pro-inflammatory phenotype and significant metabolic reprogramming. Furthermore, we found that TSPO probe high microglia are highly dependent on the Colony Stimulating Factor 1 Receptor (CSF1R) signal pathway, and selective elimination using the CSF1R inhibitor (PLX3397) reduces neuroinflammation. This study systematically decodes the TSPO signal in neuroinflammation through a multimodal approach, providing novel insights and tools for precision therapeutic strategies targeting specific pathological microglia subpopulations.
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高影响因子
ENVIRONMENTAL POLLUTION
·
2022
·
IF 9.988
Ying Tu,Yongyong Yang,Yue Wang,Nana Wu,Junyan Tao,Guanghong Yang,Mingdan You
Neurodevelopmental exposure to chlorpyrifos (CPF) could increase risks for neurological disorders, such as autism spectrum disorder, cognitive impairment, or attention deficit hyperactivity disorder. The potential involvement of microglia reactive to inflammatory stimuli in these neurological disorders has been generally reported. However, the concrete effects and potential mechanisms of microglia dysfunction triggered by developmental CPF exposure remain unclear. Therefore, we established mouse and human embryonic microglial cells (HMC3 cell) models of developmental CPF exposure to evaluate the effects of developmental CPF exposure on neuroinflammation and underlying mechanisms. The results showed that developmental exposure to CPF enhanced the expression of Iba1 in hippocampus. CPF treatment increased inflammatory cytokines levels and TSPO expression in hippocampus and HMC3 cells. The levels of necroptosis and necroptosis-related signaling RIPK/MLKL were increased in hippocampus and HMC3 cells following CPF exposure. Furthermore, the expression of TLR4/TRIF signaling was increased in hippocampus and HMC3 cells subjected to CPF exposure. Notably, the increased levels of TLR4/TRIF signaling, RIPK/MLKL signaling, necroptosis and pro-inflammatory cytokines induced by CPF treatment were remarkably inhibited by TAK-242 (a specific TLR4 inhibitor). Additionally, the necroptosis and pro-inflammatory cytokines production induced by CPF treatment were significantly relieved by Nec-1 (a specific RIPK1 inhibitor). In general, the above results suggested that activated microglia in hippocampus subjected to developmental CPF exposure underwent RIPK1/MLKL-mediated necroptosis regulated by TLR4/TRIF signaling.
研究领域:
神经科学
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毒理学
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细胞生物学
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发育生物学
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MOLECULAR PHARMACEUTICS
·
2025
·
IF 4.5
Xin Wang,Xiaotong Li,Wei Zheng,Yongzhong Zhang,Xuebo Cheng,Yajing Liu,Lu Zhang,Hualong Chen,Lin Ai,Zehui Wu
To verify its application potential in the field of cardiac and cerebral disease diagnosis, the first human experiment of [18F]BIBD-239 was reported. Synthesized via a GMP-compliant automated process on a CFN-MPS200 synthesizer (per Chinese Pharmacopoeia 2020), it achieved radiochemical purity >95%, nondecay-corrected yield >15%, and molar activity >120 GBq/μmol (total synthesis time 80 ± 5 min) under optimized conditions (95 °C, 10 min). Preclinical studies in rats confirmed TSPO-specific binding. First-in-human studies (6 healthy volunteers, 1 high-grade glioma (HGG), 1 low-grade glioma (LGG)) showed it rapidly crossed the blood–brain barrier with low normal brain retention and high sustained myocardial uptake without in vivo defluorination. HGG had higher tumor-to-background ratios (3.09) than LGG (2.33), with uptake beyond MRI-enhanced regions, correlating with histopathology. The whole-body effective dose (0.0145 ± 0.0018 mSv/MBq) was lower than [18F]FDG. [18F]BIBD-239 has robust synthesis, favorable pharmacokinetics, and TSPO-specific binding, enabling dual utility in noninvasive glioma grading and glucose-independent myocardial imaging, supporting translation in neuro-oncology and cardiovascular assessment.
研究领域:
核医学
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神经肿瘤学
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心血管影像学
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分子影像
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转化医学
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放射药学
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肿瘤诊断
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DOI
PubMed
高影响因子
Brain and Behavior
·
2024
·Vol. 14
·期 7
·e3621
·
IF 2.6
Xiang Kong,Song Luo,Shi Yao Wu,Jun Zhang,Gui Fen Yang,Guang Ming Lu,Long Jiang Zhang
Introduction Hepatic encephalopathy (HE) is a severe neuropsychiatric complication of liver diseases characterized by neuroinflammation. The efficacies of nonabsorbable rifaximin (RIF) and lactulose (LAC) have been well documented in the treatment of HE. [ 18 F]PBR146 is a translocator protein (TSPO) radiotracer used for in vivo neuroinflammation imaging. This study investigated anti-neuroinflammation effect of RIF or/and LAC in chronic HE rats by [ 18 F]PBR146 micro-PET/CT. Methods Bile duct ligation (BDL) operation induced chronic HE models, and this study included Sham+normal saline (NS), BDL+NS, BDL+RIF, BDL+LAC, and BDL+RIF+LAC groups. Behavioral assessment was performed to analyze the motor function, and fecal samples were collected after successfully established the chronic HE model (more than 28 days post-surgery). In addition, fecal samples collection and micro-PET/CT scans were performed sequentially. And we also collected the blood plasma, liver, intestinal, and brain samples after sacrificing the rats for further biochemical and pathological analyses. Results The RIF- and/or LAC-treated BDL rats showed similar behavioral results with Sham+NS group, while the treatment could not reverse the biliary obstruction resulting in sustained liver injury. The RIF or/and LAC treatments can inhibit IFN-γ and IL-10 productions. The global brain uptake values of [ 18 F]PBR146 in BDL+NS group was significantly higher than other groups ( p < .0001). The brain regions analysis showed that the basal ganglia, hippocampus, and cingulate cortex had radiotracer uptake differences among groups (all p < .05), which were consistent with the brain immunohistochemistry results. Sham+NS group was mainly enriched in Christensenella, Coprobacillus, and Pseudoflavonifractor. BDL+NS group was mainly enriched in Barnesiella, Alloprevotella, Enterococcus, and Enterorhabdus. BDL+RIF+LAC group was enriched in Parabacteroides, Bacteroides, Allobaculum, Bifidobacterium, and Parasutterella. Conclusions RIF or/and LAC had anti-neuroinflammation in BDL-induced chronic HE rats with gut microbiota alterations. The [ 18 F]PBR146 could be used for monitoring RIF or/and LAC treatment efficacy of chronic HE rats.
研究领域:
肝病学
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神经病学
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药理学
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影像科学
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微生物学
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高影响因子
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