Translational Psychiatry
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2026
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IF 7.5
Liu Yiran,Liu Xiao,Yin Xueyong,Li Yunluo,Yu Xiaohui,Nan Xinyu,Xue Jiping,Lu Hengtai,Li Bingyu,Zhou Fei,Liu Xiaoyu,Zhang Xiangyu,He Xiangjun,Yu Xi,Yan Shu,Li Yating,Wang Shuang,Gao Yuan,Liu Yifan,Kang Ying,Zhang Jingwen,Zhao Ye,Shi Haishui
Defensive aggression is an evolutionarily conserved instinct, and its dysregulation represents a common behavioral manifestation in multiple psychiatric disorders. Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for metabolic diseases, their role in aggressive behavior remains unclear. Here, we employed behavioral assays, chemogenetics, immunofluorescence, pharmacological manipulations, and metabolomics to investigate the regulatory effects of GLP-1RA on defensive aggression in mice. Acute intracerebroventricular administration of GLP-1RA significantly suppressed defensive aggression without affecting locomotor activity or time spent in the center of the open field. c-Fos immunofluorescence indicated that this effect was associated with reduced neuronal activity in the dorsomedial periaqueductal gray (DMPAG). Chemogenetic activation of DMPAG neurons reversed the suppressive effect of GLP-1RA on defensive aggression, supporting a key regulatory role of this region. In a social isolation (SI) induced pathological aggression model, GLP-1RA alleviated excessive defensive aggression and modulated the metabolic state of the DMPAG. Notably, GLP-1RA restored levels of L-carnosine, a dipeptide with neuroprotective and anti-excitotoxic properties whose levels were reduced in SI mice. Carnosine infusion into the DMPAG suppressed defensive aggression in SI mice, whereas administration of the carnosine degrading enzyme CNDP2 attenuated the suppressive effect of GLP-1RA, supporting carnosine signaling as a functionally relevant downstream component. These findings identify a carnosine-associated pathway by which GLP-1RA regulates defensive aggression and highlight its therapeutic potential beyond metabolic regulation.
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高影响因子
PHYTOMEDICINE
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2026
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IF 11.3
Jiahao Wang,Lei Peng,Haoran Sun,Jie Zeng,Rui Fu,Haonan Zhang,Rong Liang,Yan Lin,Jiazhou Ye,Liang Ma,Xiaoling Luo,Heng Jiang,Guobin Wu,Bo Qian,Rongyun Mai
Background Semen Persicae , a traditional Chinese medicine, has shown potential in alleviating metabolic dysfunction-associated fatty liver disease (MAFLD). However, the complexity of components limits its clinical application. Purpose To identify the key active component of Semen Persicae responsible for attenuating MAFLD and to elucidate the underlying mechanism. Methods The chemical components of Semen Persicae were characterized using mass spectrometry. A high-fat diet-induced MAFLD mouse model and primary liver sinusoidal endothelial cells (LSECs) were employed. Liver histopathology was used to evaluate the efficacy and safety of amygdalin (Amy). Single-cell RNA sequencing (scRNA-seq) and untargeted metabolomics analyses of mouse livers were integrated to preliminarily investigate the mechanism. Scanning electron microscopy (SEM) and assessment of fenestration markers were used to evaluate the fenestrae status of LSECs. Cytoplasmic calcium ion (Ca2+) staining, along with measurements of prostaglandin E2 (PGE2) and inositol triphosphate (IP3) levels, was applied to assess Ca2+ overload in LSECs. Results Mass spectrometry identified Amy as a major component of Semen Persicae. In a diet-induced MAFLD mouse model, Amy treatment dose-dependently attenuated disease progression, showing therapeutic efficacy comparable to liraglutide, with marked improvements in systemic metabolic parameters and significant reductions in hepatic steatosis and inflammation. Single-cell RNA sequencing identified liver sinusoidal endothelial cells (LSECs) as the most responsive cell population, with Amy markedly reducing the abundance of capillarized LSEC states. Ultrastructural analyses further demonstrated that the reduced fenestration density observed in MAFLD was substantially restored following Amy treatment. Integrated transcriptomic and metabolomic analyses revealed that arachidonic acid metabolism and endoplasmic reticulum Ca²⁺ signaling were prominently affected by Amy. In vitro experiments further confirmed that Amy reduced elevated PGE2 and IP3 levels, thereby suppressing excessive endoplasmic reticulum Ca²⁺ release. Conclusion Amy effectively ameliorates LSECs defenestration by reversing IP3-induced cytoplasmic Ca2+ overload, highlighting its potential as a plant-derived therapeutic candidate for MAFLD.
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PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
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2026
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IF 4.7
Gao Jie,Lv Xiaoyu,Zhao Pingping,Pan Bingjing,Liu Jingfang
Diabetic kidney disease (DKD) is a major microvascular complication of diabetes. The glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide exerts renoprotective effects beyond glucose control; however, the underlying mechanisms remain incompletely understood. The protective effects and mechanisms of liraglutide were investigated using in vitro (HK-2 cells under glucolipotoxic conditions) and in vivo (DKD rat) models. Key molecular and functional assessments included the evaluation of oxidative stress, apoptosis, mitochondrial function (dynamics (MFN1, MFN2, FIS1, and DRP1), mitophagy (PINK1, PARKIN, LC3II/I, and P62), and ultrastructure), and histone acetylation (H3K9/14/18/27ac). The critical role of the NQO1/SIRT3 pathway was validated using pharmacological inhibition and genetic silencing (shRNA/AAV). Both in vitro and in vivo, a multifaceted injury phenotype, including oxidative stress, apoptosis, mitochondrial dysfunction, and histone hyperacetylation, was induced, accompanied by downregulation of the NQO1/SIRT3 pathway. Disruption of this pathway further exacerbated these injuries. Conversely, liraglutide treatment effectively counteracted this phenotype, improving metabolic parameters (blood glucose, blood insulin, and blood lipids), renal function (blood urea nitrogen, serum creatinine, and urine albumin-to-creatinine ratio) and histopathology. Liraglutide attenuated oxidative stress and apoptosis, restored mitochondrial function and mitophagy, and reduced histone hyperacetylation. These protective effects were consistently associated with the restoration of NQO1/SIRT3 expression. Genetic or pharmacological disruption of the NQO1/SIRT3 axis significantly attenuated the efficacy of liraglutide, and combined inhibition completely abolished its effects. Our findings demonstrate that liraglutide attenuates DKD by activating the NQO1/SIRT3 pathway, which coordinates the enhancement of mitochondrial function and the restoration of epigenetic homeostasis. This study revealed that the NQO1/SIRT3 pathway is a critical mechanistic mediator of the renoprotective effect of liraglutide.
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高影响因子
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