EUROPEAN JOURNAL OF PHARMACOLOGY
·
2024
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IF 4.2
Yuqian Chen,Jin Liu,Qianqian Zhang,Limin Chai,Huan Chen,Danyang Li,Yan Wang,Yuanjie Qiu,Nirui Shen,Jia Zhang,Qingting Wang,Jian Wang,Xinming Xie,Shaojun Li,Manxiang Li
Stromal derived factor 1 (SDF1) has been shown to be involved in the pathogenesis of pulmonary artery hypertension (PAH). However, the detailed molecular mechanisms remain unclear. To address this, we utilized primary cultured rat pulmonary artery smooth muscle cells (PASMCs) and monocrotaline (MCT)-induced PAH rat models to investigate the mechanisms of SDF1 driving PASMCs proliferation and pulmonary arterial remodeling. SDF1 increased runt-related transcription factor 2 (Runx2) acetylation by Calmodulin (CaM)-dependent protein kinase II (CaMKII)-dependent HDAC4 cytoplasmic translocation, elevation of Runx2 acetylation conferred its resistance to proteasome-mediated degradation. The accumulation of Runx2 further upregulated osteopontin (OPN) expression, finally leading to PASMCs proliferation. Blocking SDF1, suppression of CaMKII, inhibition the nuclear export of HDAC4 or silencing Runx2 attenuated pulmonary arterial remodeling and prevented PAH development in MCT-induced PAH rat models. Our study provides novel sights for SDF1 induction of PASMCs proliferation and suggests that targeting SDF1/CaMKII/HDAC4/Runx2 axis has potential value in the management of PAH.
研究领域:
心血管疾病
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分子生物学
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药理学
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DOI
PubMed
高影响因子
Journal of Neuroinflammation
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2025
·Vol. 22
·期 1
·1-16
·
IF 10.1
Ding Peng-Fei,Zhang Jia-Tong,Zhu Xiao-Long,Cui Yue,Chen Chun-Lei,Liu Xun-Zhi,Shen Jun-Da,Zou Le-Xuan,Lu Yue,Zhuang Zong,Hang Chun-Hua,Li Wei
Background
Subarachnoid hemorrhage (SAH) is a common acute condition in neurosurgery, with microglial function playing a crucial role in determining patient outcomes. However, the involved mechanisms are complex and demand thorough investigation. In our study, we combined transcriptomic and metabolomic approaches to identify key regulators of microglial function, offering novel insights for potential therapeutic strategies in SAH treatment.
Methods
The neurological function of SAH mice was evaluated using the open field test, rotarod test, and nissl staining. In an in vitro SAH model, key pathways and genes that regulate microglial function were identified through the integration of transcriptomics and metabolomics. Enzyme-Linked Immunosorbent Assay, Immunofluorescence, Western blot, Real-Time PCR, pHrodo, and Lyso-Tracker were employed to assess lysosomal and microglial function.
Results
In SAH mice, both neurological and microglial functions were significantly impaired on the first day but showed recovery over time. The combined results from transcriptomics and metabolomics identified 5-lipoxygenase (5-LOX) as a key target in regulating microglial function post-SAH. Administering resolvin D1 (RvD1) exogenously to inhibit 5-LOX nuclear translocation or directly supplementing lipoxin A4 (LXA4) to adjust the leukotriene B4 (LTB4)/LXA4 ratio, can improve lysosomal acidification, mitigate impaired lysosomal function, and enhance phagocytosis while reducing the inflammatory response. Protecting microglial function can also be achieved through JNJ or P2X purinoceptor 7 (P2X7) siRNA, which inhibit calcium/calmodulin-dependent protein kinase II (CaMKII) activation, prevent 5-LOX nuclear translocation, and improve lysosomal function. Furthermore, P2X7 siRNA also improved neurological function, lysosomal function and microglial function in SAH mice.
Conclusion
Activation of P2X7-CaMKII after SAH promotes 5-LOX nuclear translocation, increases the LTB4/LXA4 ratio, elevates intracellular Ca2+ concentration, and impairs lysosomal and microglial function.
研究领域:
神经科学
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神经病学
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分子生物学
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免疫学
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药理学
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2020
·
IF 4.96
Nan Wang,Jue Wang,Yongjing Zhang,Yingnan Zeng,Shiling Hu,Haoyun Bai,Yajing Hou,Cheng Wang,Huaizhen He,Langchong He
Background Allergic asthma is a common inflammatory lung disease associated with complex pathogenesis. Mast cell (MC) is one of the key drivers of allergic asthma, Mas-related G protein-coupled receptor X2 (MRGPRX2) on the MC could mediate MC activation and trigger a pseudo-allergic reaction. Imperatorin (IMP), the main active compound of Radix Angelicae Dahuricae , has been reported to exert various pharmacological effects. In this study, we focused on the therapeutical mechanism of IMP on MRGPRX2-induced pseudo-allergy and allergic asthma. Methods We examined the effect of IMP on MRGPRX2 related mast cell activation in mouse peritoneal MC (MPMC), Human Laboratory of Allergic Disease 2 MCs (LAD2 cells) and Mrgprx2 -expressing HEK293 cells. Molecular docking and Surface plasmon resonance (SPR) were taken to reveal the binding character between IMP and MRPGRX2. MRGPRX2 downstream proteins were also detected by western blotting . IgE-independent responses was evaluated by using passive cutaneous anaphylaxis (PCA) and active systemic anaphylaxis (ASA) models. The therapeutic effect of IMP on asthma was evaluated by a lung inflammation mouse model which was induced by ovalbumin (OVA). Results IMP was found to reduce substance P (SP) induced calcium flux and suppressed degranulation of MC. SP can promote the phosphorylation of ERK and CamKII, which regulates the synthesis of inflammatory factors such as MIP-2 and TNF-α in MC. In vivo assays revealed that IMP can mitigate SP-induced mouse PCA and ASA. IMP could also mitigate lung inflammation in an OVA induced mice model by inhibiting MC activation in the lung tissue. Furthermore, IMP binds well to MRGPRX2 protein. The binding constant ( K D ) is 4.48 ± 0.49 × 10 −7 M. The data suggeste that IMP is a novel inhibitor of MRGPRX2 to treat allergic asthma.
研究领域:
药理学
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免疫学
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过敏
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呼吸系统疾病
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DOI
PubMed
高影响因子
BEHAVIOURAL BRAIN RESEARCH
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2020
·
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
Antioxidants
·
2021
·Vol. 10
·期 6
·930
·
IF 6.313
Nan Zhang,Shunshan Jiao,Pu Jing
Many studies have demonstrated that cabbages possess various biological activities, and our previous studies confirmed that cyanidin-3-diglucoside-5-glucoside (CY3D5G), the major core of red cabbage anthocyanins, exhibited in vitro antioxidant activity. This study further investigated the protective effects of CY3D5G derivative from red cabbage juice (RCJ) on oxidative stress and lifespan in cells andCaenorhabditis elegans, green cabbage juice (GCJ) was used as control. RCJ rather than GCJ significantly improved cell viability and decreased lactate dehydrogenase release in H2O2-induced caco-2 cells. RCJ significantly increased survival during oxidative and heat stress and mean lifespan inC. elegansby 171.63% and 31.64%, and 28.16%, respectively, while GCJ treatment showed no significant effects (p< 0.05). These results might be attributed to significantly (p< 0.05) higher contents of total phenolics, ascorbic acid, glucosinolates, and anthocyanins in RCJ compared to those in GCJ. Additionally, both of them decreased autofluorescence and reproductive capacity, increased body length, but did not alter the intracellular ROS level. Prolonged lifespan by RCJ might require heat-shock transcription factor pathway, sirtuin signaling, and calmodulin kinase II pathway, independent of insulin/insulin-like growth factor-1 signaling pathway. RCJ showed promising antioxidant properties in caco-2 cells andC. elegans, which provided more information on the health benefits of cabbage.Keywords:lifespan;anthocyanins;phytochemicals;HSP-1 pathway;CaMKII pathway;HSP-1 pathway;caco-2 cells
研究领域:
营养学
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生物化学
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分子生物学
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老年学
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DOI
PubMed
高影响因子
BIOMATERIALS
·
2026
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IF 13.6
Haiyang Gao,Wenbo Wu,Xianglong Chen,Pengzhi Shi,Anran Zhang,Wang Wu,Zimu Yu,Cao Yang,Zhangrong Cheng,Yukun Zhang
Mitochondrial dysfunction in nucleus pulposus (NP) cells is a key driver of intervertebral disc degeneration (IDD), leading to metabolic imbalance and cellular senescence. To address this, we developed an injectable "sono-electrical coupling" hydrogel (GBC@PNA) based on a thermosensitive P(NIPAM-AAM) network loaded with gallic acid, barium titanate and carbon nanotubes. Upon ultrasound exposure, the scaffold generates a localized micro-electric field and controllably releases gallic acid. This combined stimulation significantly enhanced the viability of degenerated NP cells, promoted extracellular matrix synthesis, and reduced inflammation and senescence in vitro. Mechanistically, the sono-electrical effect activated intracellular calcium signaling, leading to CaMKII-dependent mitochondrial translocation and phosphorylation of Parkin, thereby restarting PINK1/Parkin-mediated mitophagy to clear damaged mitochondria and restore energy metabolism. This pathway was systematically validated through transcriptomics, protein interaction and functional inhibition studies. In a rat IDD model, the intervention effectively maintained disc height, improved histology and delayed degeneration, demonstrating good biosafety. This work pioneers a strategy that couples external physical energy with intracellular mitochondrial quality control, offering a novel "sono-electro-chemical" therapy for IDD and a new paradigm for "energy-biology"-based tissue engineering.
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DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
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2022
·Vol. 179
·期 16
·4078-4091
·
IF 9.473
Hailou Zhang,Yan Sun,Suk-yu Yau,Yanmeng Zhou,Xinxin Song,Han-Ting Zhang,Boran Zhu,Haoxin Wu,Gang Chen
Background and Purpose Current mainstream antidepressants have limited efficacy with a delayed onset of action. Yueju, a herbal medicine, has a rapid antidepressant action. Identification of the active ingredients in Yueju and the mechanism/s involved was carried out. Experimental Approach Key molecule/s and compounds involved in this antidepressant action was identified by transcriptomic and HPLC analysis, respectively. Antidepressant effects were evaluated using various behavioural experiments. The signalling involved was assessed using site-directed pharmacological intervention or optogenetic manipulation. Key Results Transcriptomic analysis showed that Yueju up-regulated pituitary adenylate cyclase activating polypeptide (PACAP) expression in the hippocampus. Two iridoids, geniposide and shanzhiside methyl ester, were identified and quantified from Yueju. Only co-treatment with both, at an equivalent concentrations found in Yueju, increased PACAP expression and elicited a rapid antidepressant action, which were blocked by intra-dentate gyrus infusion of a PACAP antagonist or optogenetic inactivation of PACAP expressing neurons. Geniposide and shanzhiside methyl ester co-treatment rapidly inhibited CaMKII phosphorylation and enhanced mTOR/4EBP1/P70S6k/BDNF ignalling, while intra-dentate gyrus infusions of a CaMKII activator blunted the rapid antidepressant action and BDNF expression up-regulation induced by the co-treatment. A single co-treatment of them rapidly improved depression-like behaviours and up-regulated hippocampal PACAP signalling in the repeated corticosterone-induced depression model, further confirming the involvement of PACAP. Conclusion and Implications Geniposide and shanzhiside methyl ester co-treatment had a synergistic rapid onset antidepressant action by triggering hippocampal PACAP activity and associated CaMKII–BDNF signalling. This mechanism could be targeted for development of fast onset antidepressants. Graphical
研究领域:
药理学
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神经科学
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中药
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DOI
PubMed
高影响因子
Diabetes Metabolic Syndrome and Obesity-Targets and Therapy
·
2019
·
IF 3.319
Qi Feng,Chen Liu,Wei Gao,Xiao-ling Geng,Ning Dai
Purpose Oxidative stress plays an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). TRPM2 ion channel functions as a molecular sensor for oxidative stress. The aim of this study was to examine the protective effects of Salidroside, a powerful antioxidative plant, on TRPM2 in an established in vitro model of NAFLD. Methods NAFLD model was established by palmitic acid (PA) in hepatic L02 cell lines and was added to the media at a final concentration of 400 μM. Cells were used as normal group, PA group and PA receiving varied concentrations of Salidroside (75μg/mL, 150μg/mL, 300μg/mL). After treating 24 hrs, MTT assay was used to detect cell viability, and ALT level was measured using an appropriate kit assay. Intracellular lipid accumulation was observed by Oil red O staining. Cytosolic Ca 2+ concentrations were evaluated by flow cytometer with Fluo-3/AM. Quantitative RT-PCR was used to measure the mRNA expression of TRPM2, IL-1β and IL-6, and the protein expressions of TRPM2, p-CaMKII and autophagy (LC3B, p62) were determined using Western blot. Results Treatment with Salidroside effectively restored liver injury and alleviated lipid droplet deposition in a dose-dependent manner, which was associated with inhibition of TRPM2/Ca 2+ /CaMKII pathway. Additionally, autophagic clearance was enhanced by intervention with Salidroside in a dose-dependent manner. Further investigation indicated that Salidroside down-regulated the mRNA expression of IL-1β and IL-6-pro-inflammatory cytokines. Conclusion These results suggest that Salidroside could alleviate inflammatory injury and steatosis via autophagy activation mediated by downregulation of the TRPM2/Ca 2+ /CaMKII pathway. Targeting the TRPM2 ion channel is a novel treatment strategy for oxidative stress-induced liver in NAFLD.
研究领域:
药理学
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细胞生物学
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分子生物学
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肝病学
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DOI
PubMed
高影响因子
Bioactive Materials
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2024
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IF 18
Chuanlu Lin,Yiqiang Hu,Ze Lin,Longyu Du,Yixin Hu,Lizhi Ouyang,Xudong Xie,Peng Cheng,Jiewen Liao,Li Lu,Ruiyin Zeng,Ping Xia,Zhiyong Hou,Guohui Liu,Hankun Hu
Ferroptosis plays a crucial role in the progression of diabetic wounds, suggesting potential therapeutic strategies to target ferroptosis. Transient receptor potential ankyrin 1 (TRPA1) is a non-selective calcium channel that acts as a receptor for a variety of physical or chemical stimuli. Cinnamaldehyde (CA) is a specific TRPA1 agonist. In in vitro experiments, we observed that high glucose (HG) treatment induced endothelial cell ferroptosis, impairing cell function. CA successfully inhibited endothelial cell ferroptosis, improving migration, proliferation, and tube formation. Further mechanistic studies showed that CA-activated TRPA1-induced Ca 2+ influx promoted the phosphorylation of calmodulin-dependent protein kinase II (CaMKII) and nuclear factor-E 2-related factor 2 (Nrf2) translocation, which contributed to the elevation of glutathione peroxidase 4 (GPX4), leading to the inhibition of endothelial cell ferroptosis. In addition, CA was incorporated into an MMP-9-responsive injectable duplex hybrid hydrogel (CA@HA-Gel), allowing its efficient sustained release into diabetic wounds in an inflammation-responsive manner. The results showed that CA@HA-Gel inhibited wound endothelial cell ferroptosis and significantly promoted diabetic wound healing. In summary, the results presented in this study emphasize the potential therapeutic application of CA@HA-Gel in the treatment of diseases associated with ferroptosis.
研究领域:
药理学
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生物医学工程
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细胞生物学
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伤口愈合
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产品关联
DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2026
·Vol. 87
·期 1
·e70224
·
IF 4.2
Sitao Liang,Yonghua Zhu,Jiahao Su,Chuangcai Luo,Chunhong Yang
Mitochondrial dynamics play a crucial role in glioma progression by regulating cellular metabolism, proliferation, and survival. This study investigated the effects of desmopressin (dDAVP), a synthetic vasopressin analog, on mitochondrial function in human U87 MG glioma cells. Our results demonstrate that dDAVP treatment induces dose-dependent cytotoxicity while upregulating vasopressin type 2 receptor expression. The compound significantly increased oxidative stress markers and impaired mitochondrial function, as evidenced by reduced ATP production, compromised respiratory chain activity, and decreased oxygen consumption. Furthermore, dDAVP promoted mitochondrial fragmentation through Drp1 activation, enhancing its phosphorylation at Ser616 and subsequent mitochondrial translocation. Mechanistically, dDAVP was found to activate CaMKII signaling, which mediated the observed changes in Drp1 phosphorylation and mitochondrial dynamics. The CaMKII inhibitor KN-93 effectively reversed dDAVP-induced mitochondrial fragmentation, Drp1 phosphorylation, and energy metabolism impairment. The AVPR2 antagonist tolvaptan blocked dDAVP effects, confirming receptor specificity. These findings reveal that dDAVP disrupts mitochondrial homeostasis in glioma cells through AVPR2-mediated CaMKII-dependent regulation of Drp1 activity, leading to mitochondrial dysfunction and cell damage. The study provides new insights into the molecular mechanisms underlying dDAVP's effects on glioma cells and suggests potential therapeutic applications targeting the CaMKII-Drp1 axis in glioma treatment.
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PubMed
高影响因子
Journal of Environmental Sciences
·
2026
·
IF 6.5
Caiyu Lian,Mingcheng Sun,Yue Li,Lin Wang
Cadmium (Cd) exposure triggers ferroptosis in renal tubular cells. • TFRC upregulation drives Cd‑induced ferroptosis by promoting iron influx. • HIF‑1α directly binds the TFRC promoter to transactivate its expression. • mPTP‑mediated calcium efflux activates CaMKII/HIF‑1α/TFRC axis. Cadmium (Cd) is a ubiquitous environmental pollutant and well-established nephrotoxicant primarily targeting renal proximal tubular cells. Ferroptosis, an iron‑dependent form of regulated cell death driven by lipid peroxidation, has recently emerged as a key mechanism in Cd‑induced kidney injury. Despite the central role of mitochondria in ferroptosis, the precise organellar events linking Cd exposure to ferroptotic execution remain obscure. Using Sprague‑Dawley rats and renal proximal tubular cells, we found that Cd exposure instigated ferroptosis, evidenced by iron overload, altered ferroptosis markers, lipid peroxidation, and typical mitochondrial morphology under transmission electron microscopy. Pharmacological inhibition of ferroptosis significantly attenuated Cd‑induced cellular damage, identifying ferroptosis as a critical driver. Mechanistically, Cd triggered opening of the mitochondrial permeability transition pore (mPTP), leading to mitochondrial calcium efflux and activation of calcium/calmodulin‑dependent protein kinase II (CaMKII). Activated CaMKII in turn increased hypoxia-inducible factor-1α (HIF-1α) transcription and promoted its nuclear accumulation. Notably, upregulated HIF‑1α directly bound to the promoter of transferrin receptor (TFRC) to stimulate expression of this key iron transport mediator, as confirmed by chromatin immunoprecipitation assay. Moreover, genetic knockdown of TFRC markedly attenuated Cd‑triggered ferroptosis and consequent cytotoxicity, establishing TFRC as a critical executioner of Cd‑evoked renal injury. Taken together, these findings delineate a novel signaling axis from mPTP‑mediated calcium efflux to HIF‑1α‑dependent TFRC transactivation that drives ferroptosis in Cd‑induced nephrotoxicity, offering a mechanistic basis for understanding and mitigating the renal health risks posed by environmental Cd exposure. Download: Download high-res image (405KB) Download: Download full-size image
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Frontiers in Behavioral Neuroscience
·
2021
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IF 3.558
Yin Ying,Qian Shiyu,Chen Yifan,Sun Yan,Li Yuqiao,Yu Yongfei,Li Jianqing,Wu Zhangjie,Yu Xinlang,Ge Rui,Han Jia,Sun Dongdong,Wu Haoxin,Liu Lanying,Xue Wenda,Wang Wei
Previous studies have demonstrated that Yueju-Ganmaidazao (YG) decoction induces rapid antidepressant-like effects, and the antidepressant response is mostly dependent on the suppression of nitric oxide-cyclic guanosine monophosphate signaling in male mice. This study aimed to investigate the sex difference mediated by calcium/calmodulin-dependent protein kinase II (CaMKII)-neuronal nitric oxide synthase (nNOS) signaling involved in the antidepressant-like effect of YG in mice. We found that the immobility times in the tail suspension test (TST) were found to be decreased after the single injection of YG in male and female mice with the same dosage. Additionally, chronic administration for 4 days of subthreshold dosage of YG and escitalopram (ES) also significantly decreased the immobility time in mice of both sexes. Chronic subthreshold dosage of YG and ES in LPS-treated mice and in chronic unpredictable stress (CUS) mice both decreased the immobility time, which was increased by stress. Meanwhile, in CUS-treated mice, sucrose preference test, forced swimming test, and open field test were applied to further confirm the antidepressant-like effects of YG and ES. Moreover, CUS significantly decreased the expression of nNOS and CaMKII, and both YG and ES could enhance the expression in the hippocampus of female mice, which was opposite to that in male mice, while endothelial nitric oxide synthase expression was not affected by stress or drug treatment neither in male mice nor in female mice. Finally, subthreshold dosage of YG combined with 7-nitroindazole (nNOS inhibitor) induced the antidepressant-like effects both in female and in male mice, while the single use of YG or 7-NI did not display any effect. However, pretreatment with KN-93 (CaMKII inhibitor) only blocked the antidepressant-like effect of high-dosage YG in female mice. Meanwhile, in CUS mice, chronic stress caused NR1 overexpression and inhibited cAMP response element binding protein action, which were both reversed by YG and ES in male and female mice, implying that YG and ES produced the same antidepressant-like effect in mice of both sexes. The study revealed that chronic treatment with a subthreshold dose of YG also produced antidepressant-like effects in female mice, and these effects depended on the regulation of the CaMKII-nNOS signaling pathway.
研究领域:
药理学
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神经科学
·
行为科学
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DOI
PubMed
高影响因子
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