Journal of Neuroinflammation
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2022
·Vol. 19
·期 1
·1-14
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IF 9.587
Lan Tian,Wu Yuhan,Zhang Yulei,Li Shuhan,Zhu Zhanpeng,Wang Liyan,Mao Xueqin,Li Ye,Fan Cuiqin,Wang Wenjing,Yu Shu Yan
Background Agomelatine has been shown to be effective in the treatment of depression, but the molecular mechanisms underlying its antidepressant effects have yet to be elucidated. Identification of these molecular mechanisms would not only offer new insights into the basis for depression but also provide the foundation for the development of novel treatments for this disorder.
Methods Intraperitoneal injection of LPS was used to induce depression-like behaviors in rats. The interactions of the 5-HT2C reporter and Gαi-2 were verified by immunoprecipitation or immunofluorescence assay. Inflammatory related proteins, autophagy related proteins and apoptosis markers were verified by immunoblotting or immunofluorescence assay. Finally, electron microscopy analysis was used to observe the synapse and ultrastructural pathology. Results Here, we found that the capacity for agomelatine to ameliorate depression and anxiety in a lipopolysaccharide (LPS)-induced rat model of depression was associated with an alleviation of neuroinflammation, abnormal autophagy and neuronal apoptosis as well as the promotion of neurogenesis in the hippocampal dentate gyrus (DG) region of these rats. We also found that the 5-HT2C receptor is coupled with G alphai (2) (Gαi-2) protein within hippocampal neurons and, agomelatine, acting as a 5-HT2C receptor antagonist, can up-regulate activity of the Gαi-2-cAMP-PKA pathway. Such events then suppress activation of the apoptosis signal-regulating kinase 1 (ASK1) pathway, a member of the mitogen-activated protein kinase (MAPK) family involved in pathological processes of many diseases. Conclusion Taken together, these results suggest that agomelatine plays a neuroprotective role in regulating neuroinflammation, autophagy disorder and apoptosis in this LPS-induced rat model of depression, effects which are associated with the display of antidepressant behaviors. These findings provide evidence for some of the potential mechanisms for the antidepressant effects of agomelatine. Graphical Abstract
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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行为科学
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DOI
PubMed
高影响因子
BEHAVIOURAL BRAIN RESEARCH
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2020
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IF 2.977
Yuan-Jian Song,Yue Shi,Miao-Miao Cui,Man Li,Xiang-Ru Wen,Xiao-Yan Zhou,He-Qing Lou,Yu-Lan Wang,Da-Shi Qi,Man Tang,Xun-Bao Zhang
Cerebral ischemia/reperfusion (I/R) injury is a leading cause of learning and memory dysfunction. Hydrogen sulfide (H 2 S) has been shown to confer neuroprotection in various neurodegenerative diseases, including cerebral I/R-induced hippocampal CA1 injury. However, the underlying mechanisms have not been completely understood. In the present study, rats were pretreated with SAM/NaHS (SAM, an H 2 S agonist, and NaHS, an H 2 S donor) only or SAM/NaHS combined with CaM (an activator of CaMKII) prior to cerebral ischemia. The Morris water maze test demonstrated that SAM/NaHS could alleviate learning and memory impairment induced by cerebral I/R injury. Cresyl violet staining was used to show the survival of hippocampal CA1 pyramidal neurons. SAM/NaHS significantly increased the number of surviving cells, whereas CaM weakened the protection induced by SAM/NaHS. The immunohistochemistry results indicated that the number of Iba1-positive microglia significantly increased after cerebral I/R. Compared with the I/R group, the number of Iba1-positive microglia in the SAM/NaHS groups significantly decreased. Co-Immunoprecipitation and immunoblotting were conducted to demonstrate that SAM/NaHS suppressed the assembly of CaMKII with the ASK1-MKK3-p38 signal module after cerebral I/R, which decreased the phosphorylation of p38. In contrast, CaM significantly inhibited the effects of SAM/NaHS. Taken together, the results suggested that SAM/NaHS could suppress cerebral I/R injury by downregulating p38 phosphorylation via decreasing the assembly of CaMKII with the ASK1-MKK3-p38 signal module.
研究领域:
神经科学
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药理学
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神经保护
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信号转导
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2025
·Vol. 26
·期 4
·1527
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IF 4.9
Lingzhi Wang,Yalei Gao,Yuying Chen,Zhenzhou Tang,Xiao Lin,Meng Bai,Pei Cao,Kai Liu
Apoptosis signal-regulating kinase 1 (ASK1), a key component of the mitogen-activated protein kinase (MAPK) cascades, has been identified as a promising therapeutic target owing to its critical role in signal transduction pathways. In this study, we proposed novel pyridin-2-yl urea inhibitors exhibiting favorable physicochemical properties. The potency of these compounds was validated through in vitro protein bioassays. The inhibition (IC50) of compound2was 1.55 ± 0.27 nM, which was comparable to the known clinical inhibitor, Selonsertib. To further optimize the hit compounds, two possible binding modes were initially predicted by molecular docking. Absolute binding free energy (BFE) calculations based on molecular dynamics simulations further discriminated the binding modes, presenting good tendency with bioassay results. This strategy, underpinned by BFE calculations, has the great potential to expedite the drug discovery process in the targeting of ASK1 kinase.
研究领域:
药理学
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药物化学
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计算生物学
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药物发现
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2026
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IF 4.7
Shasha Zhang,Huilin Sun,Xinran Li,Kunmei Xie,Yusa Li,Hongyu Huang,Huizhen Chen,Jingquan Dong
Sepsis is a severe systemic inflammatory condition characterized by infection, and marked by high morbidity and mortality. Injury to the spleen resulting from sepsis disrupts immune defense functions, exacerbates systemic inflammatory dysregulation, and contributes to multiple organ failure, thereby substantially increasing patient mortality. Sophoridine (SR), a naturally occurring alkaloid derived from Sophora flavescens , exhibits anti-inflammatory, antioxidant and neuroprotective effects. This study investigated the protective effects of SR against sepsis-induced splenic damage and elucidated its underlying mechanisms. A murine sepsis model was established using cecal ligation and puncture (CLP), and SR was administered to assess its efficacy. Histological analysis demonstrated that SR markedly ameliorated structural damage to splenic tissue in mice subjected to CLP. Quantitative PCR (qPCR), dihydroethidium (DHE) staining, and TUNEL assays revealed that SR significantly reduced the mRNA levels of pro-inflammatory mediators, including Tnf , Il6 , Il1b and Nos2 , while increasing the mRNA level of the anti-inflammatory mediator Il10 . Furthermore, SR substantially reduced reactive oxygen species (ROS) production and apoptosis. We also established an in vitro model by stimulating J774A.1 cells with lipopolysaccharide (LPS). Results from Western blotting, qPCR and flow cytometry analyzes indicated that the beneficial effects of SR on LPS-induced inflammation, oxidative stress and apoptosis were substantially attenuated by overexpression of ASK1. In conclusion, SR alleviates sepsis-induced splenic injury by suppressing inflammation, oxidative stress, and apoptosis through the inhibition of ASK1, thereby offering a potential therapeutic approach for the management of splenic injury in sepsis.
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DOI
PubMed
高影响因子
CELL CYCLE
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2021
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IF 4.534
Yanming Yu,Daoxu Wu,Yongwei Li,Hui Qiao,Zhengfei Shan
Background Ketamine-related cystitis (KC) has been researched in many clinical studies, but its exact mechanism is ambiguous and needs further research. Methods We established a KC rat model and analyzed physiological, biochemical, and urodynamic parameters of ketamine (KET)-related bladder injury. Bladder histologic feature, reactive oxygen species (ROS), autophagy-, apoptosis-, and endoplasmic reticulum stress (ERS)-related markers were examined by hematoxylin and eosin staining, Masson staining, ROS kit, quantitative real-time polymerase chain reaction, and western blot. In vitro, effects of 0.01, 0.1, and 1 mM KET on cell vitality, apoptosis, ROS level, autophagy-, apoptosis-, and ERS-related markers were examined again. Effects of KET-1 and salubrinal on complex formation, autophagy-, apoptosis-, and ERS-related markers were examined by Co-Immunoprecipitation and western blot. After transfection with shIRE1, complex formation, cell biological behaviors, ROS level, autophagy-, apoptosis-, and ERS-related markers were examined again. Results KET induced bladder hyperactivity and injury. KET facilitated urinary frequency, ROS production, and induced bladder histologic injury by activating autophagy-, apoptosis-, and ERS-related markers in rats. In vitro, KET (0.01, 0.1, and 1 mM) restrained cell vitality and elevated apoptosis and ROS level via activating autophagy-, apoptosis-, and ERS-related markers. Moreover, salubrinal reversed the promotion of KET-1 on complex formation, autophagy-, apoptosis-, and ERS-related marker expressions. After transfection with shIRE1, shIRE1 weakened complex formation induced by KET-1, and the effects of KET-1 on cells were offset by shIRE1. Conclusion KET enhanced autophagy and ERS in vivo and in vitro via restraining IRE1-TRAF2-ASK1-JNK pathway.
研究领域:
药理学
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泌尿学
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细胞生物学
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DOI
PubMed
高影响因子
Bioengineering & Translational Medicine
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2024
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IF 6.1
Juan Deng,Juan Qin,Guolin Song,Chenghai Li,Wentao Tang,Yilin Tang,Xinfang Xiao,Liu Wu,Sicheng He,Yiqing Zhou,Junfen Li,Yan Wang
The potential of low-intensity pulsed ultrasound (LIPUS) in regulating ovarian function has been demonstrated; however, there is a lack of scientific evidence regarding the long-term efficacy of LIPUS in treating ovarian injury and understanding its regulatory mechanisms. In this study, 4-vinylcyclohexene diepoxide (VCD) was used to induce ovarian injury in rats, and LIPUS was applied to target the damaged ovarian tissues. The research aimed to investigate the long-term protective effect of LIPUS against ovum toxicity induced by VCD and elucidate the associated molecular mechanisms. During the experiment, HE staining was employed for observing the morphology and structure of the ovary, while protein sequencing was utilized for identifying and confirming the molecular mechanism through which LIPUS restores the damaged ovarian structure. The long-term effectiveness of LIPUS in protecting against ovarian injury was evaluated through ELISA, estrous cycle monitoring, fertility testing, and behavioral analysis. The results indicated that LIPUS effectively restored the structure of damaged ovaries. Both in vivo and in vitro studies revealed that this protective effect may be attributed to LIPUS inhibiting apoptosis of ovarian granulosa cells (GCs) by regulating Daxx-mediated ASK1/JNK signaling pathway. Subsequent functional tests demonstrated significant improvements in sex hormone secretion and regulation of estrous cycle within 6 cycles following LIPUS treatment. Additionally, there was a notable increase in offspring numbers after mating. Behavioral analysis revealed that LIPUS effectively alleviated menopausal symptoms resulting from ovarian injury including mood fluctuations, cognitive behavior changes, and reduced muscle excitability levels. These findings suggest that beneficial effects of LIPUS may help reduce VCD-induced ovarian damage with long-term efficacy.
研究领域:
生殖医学
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分子生物学
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内分泌学
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DOI
高影响因子
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